Modulators of peroxisome proliferator activated receptors

ABSTRACT

Disclosed is a compound represented by Structural Formula (I): Ar is a substituted or unsubstituted aromatic group. Q is a covalent bond, —CH 2 — or —CH 2 CH 2 —; W is a substituted or unsubstituted alkylene or a substituted or unsubstituted heteroalkylene linking group from two to ten atoms in length, preferably from two to seven atoms in length. Phenyl Ring A is optionally substituted with up to four substituents in addition to R 1  and W, R 1  is (CH 2 ) n —CH(OR 2 )—(CH 2 ) m E 1 , —(CH)═C(OR 2 )—(CH 2 ) m E, —(CH 2 ) n —CH(Y)—(CH 2 ) m E or (CH)═C(Y)—(CH 2 ) m E; wherein E is COOR 3 , C 1 –C 3  alkylnitrile, carboxamide, sulfonamide, acylsulfonamide or tetrazole and wherein sulfonamide, acylsulfonamide and tetrazole are optionally substituted with one or more substituents independently selected from: C 1 –C 6  alkyl, haloalkyl and aryl-C 0 -4-alkyl; R 2  is H, an aliphatic group, a substituted aliphatic group, haloalkyl, an aromatic group, a substituted aromatic group, —COR 4 , —COOR 4 , —CONR 5 R 6 , —C(S)R 4 , —C(S)OR 4  or C(S)NR 5 R 6 , R 3  is H, an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. Y is O—, CH 2 —, —CH 2 CH 2 — or CH═CH— and is bonded to a carbon atom in Phenyl Ring A that is ortho to R 1 . R 4 –R 6  are independently H, an aliphatic group, a substituted aliphatic group, an aromatic group or a substituted aromatic group. n and m are independently 0, 1 or 2

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application60/297,144, filed 7 Jun. 2001, the entire teachings of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

The peroxisome proliferator activated receptors (PPARs) are members ofthe nuclear receptor gene family that are activated by fatty acids andfatty acid metabolites. The PPARs belong to the subset of nuclearreceptors that function as heterodimers with the 9-cis retinoic acidreceptor (RXR). Three subtypes, designated PPARα, PPARγ and PPARδ, arefound in species ranging from Xenopus to humans.

PPARα is the main subtype in the liver and has facilitated analysis ofthe mechanism by which peroxisome proliferators exert their pleiopropiceffects. PPARα is activated by a number of medium and long-chain fattyacids, and it is involved in stimulating β-oxidation of fatty acids.PPARα is also involved with the activity of fibrates and fatty acids inrodents and humans. Fibric acid derivatives such as clofibrate,fenofibrate, bezafibrate, ciprofibrate, beclofibrate and etofibrate, aswell as gemfibrozil, produce a substantial reduction in plasmatriglycerides along with moderate reduction in low-density lipoprotein(LDL) cholesterol, and they are used particularly for the treatment ofhypertriglyceridemia.

PPARγ is the main subtype in adipose tissue and involved in activatingthe program of adipocyte differentiation. PPARγ is not involved instimulating peroxisome proliferation in the liver. There are two isomersof PPARγ: PPARγ1 and PPARγ2, which differ only in that PPARγ2 containsan additional 28 amino acids present at the amino terminus. The DNAsequences for the PPARγ receptors are described in Elbrecht, et al.,BBRC 224; 431–437 (1996). Although peroxisome proliferators, includingthe fibrates and fatty acids, activate the transcriptional activity ofPPAR's, only prostaglandin J₂ derivatives have been identified asnatural ligands for PPARγ, which also binds the anti-diabetic agentsthiazolidinediones with high affinity. The physiological functions ofPPARα and PPARγ in lipid and carbohydrate metabolism were uncovered onceit was recognized that they were the receptors for the fibrate andglitazone drugs, respectively.

PPARα and PPARγ receptors have been implicated in diabetes mellitus,cardiovascular disease, obesity, and gastrointestinal disease, such asinflammatory bowel disease and other inflammation related illnesses.Such inflammation related illnesses include, but are not limited toAlzheimer's disease, Crohn's disease, rheumatoid arthritis, psoriasis,and ischemia reprofusion injury. By contrast, PPARδ (also referred to asPPARβ and NUC1) is not reported to be receptor for any known class ofdrug molecules, and its role in mammalian physiology has remainedundefined. The human nuclear receptor gene PPARδ (hPPARδ) has beencloned from a human osteosarcoma cell cDNA library and is fullydescribed in A. Schmidt et al., Molecular-Endocrinology, 6:1634–1641(1992).

Diabetes is a disease in which a mammal's ability to regulate glucoselevels in the blood is impaired because the mammal has a reduced abilityto convert glucose to glycogen for storage in muscle and liver cells. InType I diabetes, this reduced ability to store glucose is caused byreduced insulin production. “Type II Diabetes” or “non-insulin dependentdiabetes mellitus” (NIDDM) is the form of diabetes, which is due to apropound resistance to insulin stimulating or regulatory effect onglucose and lipid metabolism in the main insulin-sensitive tissues,muscle, liver and adipose tissue. This resistance to insulinresponsiveness results in insufficient insulin activation of glucoseuptake, oxidation and storage in muscle and inadequate insulinrepression of lipolysis in adipose tissue and of glucose production andsecretion in liver. When these cells become desensitized to insulin, thebody tries to compensate by producing abnormally high levels of insulinand hyperinsulemia results. Hyperinsulemia is associated withhypertension and elevated body weight. Since insulin is involved inpromoting the cellular uptake of glucose, amino acids and triglyceridesfrom the blood by insulin sensitive cells, insulin insensitivity canresult in elevated levels of triglycerides and LDL (known as the “bad”cholesterol) which are risk factors in cardiovascular diseases. Theconstellation of symptoms which includes hyperinsulemia combined withhypertension, elevated body weight, elevated triglycerides and elevatedLDL is known as Syndrome X.

Hyperlipidemia is a condition which is characterized by an abnormalincrease in serum lipids, such as cholesterol, triglycerides andphospholipids. These lipids do not circulate freely in solution inplasma, but are bound to proteins and transported as macromolecularcomplexes called lipoproteins. One form of hyperlipidemia ishypercholesterolemia, characterized by the existence of elevated LDLcholesterol levels. The initial treatment for hypercholesterolemia isoften a diet low in fat and cholesterol coupled with appropriatephysical exercise. Drug intervention is initiated if LDL-lowering goalsare not met by diet and exercise alone. It is desirable to lowerelevated levels of LDL cholesterol and increase levels of HDLcholesterol. Generally, it has been found that increased levels of HDLare associated with lower risk for coronary heart disease (CHD). SeeGordon, et al., Am. J. Med., 62, 707–714 (1977); Stampfer, et al., N.England J. Med., 325, 373–381 (1991); and Kannel, et al., Ann. InternalMed., 90, 85–91 (1979). An example of an HDL raising agent is nicotinicacid, but the quantities needed to achieve HDL elevation are associatedwith undesirable effects, such as flushing.

There are several treatments currently available for treating diabetesmellitus but these treatments still remain unsatisfactory and havelimitations. While physical exercise and reduction in dietary intake ofcalories will improve the diabetic condition, compliance with thisapproach can be poor because of sedentary lifestyles and excess foodconsumption, in particular high fat-containing food. Therefore treatmentwith hypoglycemics, such as sulfonylureas (e.g., chlorpropamide,tolbutamide, tolazamide and acetohexamide) and biguanides (e.g.phenformin and metformin) are often necessary as the disease progresses.Sulfonylureas stimulate the β cells of the pancreas to secrete moreinsulin as the disease progresses. However, the response of the β cellseventually fails and treatment with insulin injections is necessary. Inaddition, both sulfonylurea treatment and insulin injection have thelife threatening side effect of hypoglycemic coma, and thus patientsusing these treatments must carefully control dosage.

It has been well established that improved glycemic control in patientswith diabetes (Type I and Type II) is accompanied by decreasedmicrovasclular complications (DCCT and UKPDS). Due to difficulty inmaintaining adequate glycemic control over time in patients with Type IIdiabetes, the use of insulin sensitizers in the therapy of Type IIdiabetes is growning. There is also a growing body of evidence thatPPARγ agonist, insulin sensitizer, may have benefits in the treatment ofType II diabetes beyond their effects in improving glycemic control.

In the last decade a class of compounds known as thiazolidinediones(e.g. U.S. Pat. Nos. 5,089,514; 4,342,771; 4,367,234; 4,340,605; and5,306,726) have emerged as effective anidiabetic agents that have beenshown to increase the sensitivity of insulin sensitive tissues, such asskeletal muscle, liver and adipose, to insulin. Increasing insulinsensitivity rather than the amount of insulin in the blood reduces thelikelihood of hypoglycemic coma. Although thiazolidinediones have beenshown to increase insulin sensitivity by binding to PPARγ receptors,this treatment also produces unwanted side effects such as weight gainand, for troglitazone, liver toxicity.

In view of the above, there exists a need for new pharmaceutical agentswhich modulate these receptors to prevent, treat and/or alleviate thesediseases or conditions while ameliorating side effects of currenttreatments.

SUMMARY OF THE INVENTION

Disclosed herein are novel α-methoxy cinnamates which are modulators ofperoxisome proliferator activated receptors (PPAR). Many of these novelα-methoxy cinnamates have the advantage over previously known PPARmodulators in that they selectively bind at peroxisome proliferatoractivated receptor modulators. Based on this discovery, methods ofmodulating a peroxisome proliferator activated receptor in a subject inneed of such modulation, methods of treating a subject for Type IIdiabetes, methods of treating a subject for cardiovascular disease,methods of treating a subject for Syndrome X and methods of treating asubject with other PPAR-mediated diseases and conditions are disclosedherein.

One embodiment of the present invention is a compound represented byStructural Formula (I):

The variables in Structural Formula (I) are defined below.

Ar is a substituted or unsubstituted aromatic group. Preferably, Ar isan unsubstituted, monosubstituted or disubstituted aromatic group.

Q is a covalent bond, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂—.Preferably, Q is a covalent bond.

W is a substituted or unsubstituted alkylene group two to ten atoms inlength or a substituted or unsubstituted heteroalkylene group, whereinthe heteroalkylene group is an alkylene group from two to ten atoms inlength in which one or more methylene groups have been replaced with afunctional group selected from —CH═CH—, —C≡C—, —O—, —CO—, —NR₇—,—NR₇CO—, —C(═NOH)—, —S—, —S(O)—, —S(O)₂— or —CH(NR₇R₈)—.

Phenyl Ring A is optionally substituted with up to four substituents inaddition to R₁ and W.

R₁ is —(CH₂)_(n)—CH(OR₂)—(CH₂)_(m)E, —(CH)═C(OR₂)—(CH₂)_(m)E,—(CH₂)_(n)—CH(Y)—(CH₂)_(m)E or —(CH)═C(Y)—(CH₂)_(m)E. E is COOR₃,C1–C3-alkylnitrile, carboxamide, sulfonamide, acylsulfonamide ortetrazole and wherein sulfonamide, acylsulfonamide and tetrazole areoptionally substituted with one or more substituents independentlyselected from: C1–C6 alkyl, C1–C6 haloalkyl and aryl-C0–4-alkyl.Preferably R₁ is —(CH₂)_(n)—C(OR₂)—(CH₂)_(m)COOR₃,—(CH)═C(OR₂)—(CH₂)_(m)COOR₃, —(CH₂)_(n)—CH(Y)—(CH₂)_(m)COOR₃ or—(CH)═C(Y)—(CH₂)_(m)COOR₃. More preferably R₁ is meta or para to W andis represented by Structural Formula (II), even more preferably byStructural Formulas (III) or (IV) and even more preferably by StructuralFormula (V):

R₂ is —H, an aliphatic group, a substituted aliphatic group, haloalkyl,an aralkyl group, a substituted aralkyl group, an aromatic group, asubstituted aromatic group, —COR₄, —COOR₄, —CONR₅R₆, —C(S)R₄, —C(S)OR₄or —C(S)NR₅R₆.

Y is —O—, —CH₂—, —CH₂CH₂— or a —CH═CH— group that is bonded to a carbonatom in Phenyl Ring A that is ortho to R₁. Thus, Y, together with thetwo carbon atoms to which Y is bonded and the intervening carbon atoms,form a ring that is fused to Phenyl Ring A.

R₃–R₈ are independently —H, an aliphatic group, a substituted aliphaticgroup, an aromatic group or a substituted aromatic group.

n and m are independently 0, 1 or 2.

In Structural Formula (I), preferably, R₂ is a C1–C6 lower alkyl group,phenyl, benzyl or benzoyl; and R₃ is —H or a C1–C6 alkyl group (morepreferably C₁–C₃ alkyl group).

In another embodiment, the compound of the present invention isrepresented by Structural Formula (VI):

The variables in Structural Formula (VI) are defined below.

Ar is a substituted or unsubstituted aromatic group. Preferably, Ar isan unsubstituted, monosubstituted or disubstituted aromatic group.

W is a substituted or unsubstituted alkylene linking group or asubstituted or unsubstituted heteroalkylene linking group from two toten atoms in length, preferably from two to seven atoms in length.

Phenyl Ring A is optionally substituted with up to four substituents inaddition to R₁.

R₁ is —(CH₂)_(n)—CH(OR₂)—(CH₂)_(m)COOR₃, —(CH)═C(OR₂)—(CH₂)_(m)COOR₃,—(CH₂)_(n)CH(Y)—(CH₂)_(m)COOR₃ or —(CH)═C(Y)—(CH₂)_(m)COOR₃. PreferablyR₁ is meta or para to W and is represented by Structural Formula (II),more preferably by Structural Formula (III) and even more preferably byStructural Formula (IV). Structural Formulas (II)–(V) are shown above.

R₂ is —H, an aliphatic group, a substituted aliphatic group, an arylgroup, a substituted aryl group, —COR₄, —COOR₄, —CONR₅R₆, —C(S)R₄,—C(S)OR₄ or —C(S)NR₅R₆.

Y is —O—, —CH₂—, —CH₂CH₂— or —CH═CH— and is bonded to a carbon atom inPhenyl Ring A that is ortho to R₁.

R₃–R₆ are independently —H, an aliphatic group, a substituted aliphaticgroup, an aryl group or a substituted aryl group.

n and m are independently 0, 1 or 2.

In Structural Formula (VI), preferably, R₂ is a C1–C6 lower alkyl group,phenyl, benzyl or benzoyl; and R₃ is —H or a C₁–C₃ lower alkyl group.

Another embodiment of the present invention is a method of modulating aperoxisome proliferator activated receptor (PPAR). The method comprisesthe step of contacting the receptor with at least one of the compoundsof the present invention.

Another embodiment of the present invention is a method of modulating aperoxisome proliferator activated receptor gamma in a subject in need ofmodulation of the peroxisome proliferator activated receptor gamma,i.e., treating a PPAR-gamma mediated disease in a subject. The methodcomprises the step of administering to the subject an effective amountof a compound of the present invention.

Another embodiment of the present invention is a method for loweringblood-glucose in a subject in need of such treatment. The methodcomprises the step of administering to the subject an effective amountof a compound of the present invention.

Another embodiment of the present invention is a method of treating asubject for hyperglycemia, dyslipidemia, Type II diabetes, Type Idiabetes, hypertriglyceridemia, syndrome X, insulin resistance, heartfailure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia,hypertension, obesity, anorexia bulimia, polycystic ovarian syndrome,anorexia nervosa, cardiovascular disease or other diseases where insulinresistance is a component. The method comprises the step ofadministering to the subject an effective amount of a compound of thepresent invention.

Another embodiment of the present invention is a method of treating asubject with diabetes mellitus. The method comprises the step ofadministering to the subject an effective amount of a compound of thepresent invention

Another embodiment of the present invention is a method of treating asubject for cardiovascular disease. The method comprises the step ofadministering to the subject an effective amount of a compound of thepresent invention.

Another embodiment of the present invention is a method of treating asubject for Syndrome X. The method comprises the step of administeringto the subject an effective amount of a compound of the presentinvention.

Another embodiment of the present invention is a compound of the presentinvention for use in therapy. The therapy can be, for example, to treatType II diabetes, cardiovascular disease, Syndrome X or a disordermodulated by a peroxisome proliferator activated receptor.

Another embodiment of the present invention is the use of a compound ofthe present invention for the manufacture of a medicament for thetreatment of hyperglycemia, dyslipidemia, Type II diabetes, Type Idiabetes, hypertriglyceridemia, syndrome X insulin resistance, heartfailure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia,hypertension, obesity, anorexia bulimia, polycystic ovarian syndrome,anorexia nervosa, cardiovascular disease or other diseases where insulinresistance is a component or other disorders modulated by a peroxisomeproliferator activated receptor.

Yet another embodiment of the present invention is a pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier and atleast one compound of the present invention.

Yet another embodiment of the present invention is a method of preparinga compound represented by Structural Formula (VII) from a startingcompound represented by Structural Formula (VIII):

The method comprises the step of hydrolyzing the ester group in thestarting compound. Phenyl Ring A, Ar, Q, W, R₂ and R₃ are as describedfor Structural Formulas (I) or (VI). Q in Structural Formulas (VII) and(VIII) is preferably a covalent bond.

Yet another embodiment of the present invention is one of the novelcompounds described herein, wherein the compound is radioactivelylabeled, i.e., comprises a radioactive isotope (e.g., ³H or ¹⁴C) at aspecific site in the compound at level significantly greater than thenatural abundance of the isotope. “Significantly greater than naturalabundance” means that the amount of isotope greater than naturalabundance can be assessed by suitable means (e.g., scintillationcounting). Radiolabeled, preferably tritiated,(S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acidis one example of a radiolabeled compound of the invention. Radiolabeledcompounds, can be advantageously used to assess binding of test compoundto PPARγ.

Yet another embodiment of the present invention is a method fordetermining whether a compound does or does not interact directly (e.g.,binds) with PPARγ. The method comprises the step of specifically bindinga radioactively labeled compound described herein to the ligand bindingdomain of a PPARγ receptor. The receptor is then combined with a testcompound and the amount of specific binding of the radioactively labeledcompound is assessed. Any decrease in the binding of the radiolabeledcompound indicates that the test compound interacts directly with theperoxisome proliferator-activated receptor.

The compounds of the present invention and pharmaceutically acceptablesalts, solvates and hydrates, stereoisomers thereof lower one or more ofthe following in mammals: glucose, insulin, triglycerides, fatty acidsand/or cholesterol. They are therefore believed to be effective intreating hyperglycemia, dyslipidemia, Type II diabetes, Type I diabetes,hypertriglyceridemia, syndrome X insulin resistance, heart failure,diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension,obesity, anorexia bulimia, polycystic ovarian syndrome, anorexianervosa, cardiovascular disease or other diseases where insulinresistance is a component or other disorders modulated by a peroxisomeproliferator activated receptor.

DETAILED DESCRIPTION OF THE INVENTION

In the Schemes, Preparations and Examples below, various reagent symbolsand abbreviations have the following meanings:

BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl Boc t-butoxycarbonylCBZ benzyloxycarbonyl DCM dichloromethane DEAD diethyl azodicarboxylateDIAD diisopropyl azodicarboxylate DIPEA diisopropylethylamine DMAP4-dimethylamino pyridine DMF N,N-dimethylformamide DMSOdimethylsulfoxide eq. equivalent(s) EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl ESI-MS electron sprayion-mass spectroscopy Et ethyl EtOAc ethyl acetate FMOC9-Flurorenylmethyl carbamate HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HOAT:1-hydroxy-7-azabenzotriazole HOBT 1-hydroxybenzotriazole hydrate HPLChigh performance liquid chromatography HRMS high resolution mass LRMSlow resolution mass Me methyl Ms methanesulfonyl Pd₂(dba)₃tris(dibenzylideneacetone) dipalladium(0) Ph phenyl Phe phenylalanine Prpropyl r.t. room temperature TBAF tetrabutylammonium fluoride TBStertbutyldimethylsilyl TFA trifluoroacetic acid TEA triethylamine THFtetrahydrofuran Tic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid TLCthin-layer chromatography

In one preferred embodiment, the compound of the present invention isrepresented by Structural Formula (IX):

Ar, Phenyl Ring A and R₁ in Structural Formula (IX) are as defined inStructural Formulas (I) or (VI). R₁ is preferably para to W₁ and isrepresented by Structural Formula (II), more preferably StructuralFormulas (III) or (IV) and even more preferably, Structural Formula (V).

p is an integer from one to nine, preferably one to four.

W₁ is —O—, —C(O), —OCH₂—, —CH₂—, —NR₈—, —NR₈CO—, —NR₈CH—, —C(═NOH)— or—CH(NR₇R₈)—.

R₇ and R₈ are independently —H, an aliphatic group, a substitutedaliphatic group, an aromatic group or a substituted aromatic group.

In a more preferred embodiment, the compound of the present invention isrepresented by a structural formula selected from Structural Formulas(X)–(XVIII):

Ar, Phenyl Ring A, R₂ and R₃ in Structural Formulas (X)–(XIX) are asdescribed for Structural Formula (IX). Preferably, R₂ and R₃ are asdescribed for Structural Formula (II). More preferably, —CH₂CH(OR₂)COOR₃in Structural Formulas (X)–(XIX) is represented by Structural Formulas(III) or (IV) and even more preferably by Structural Formula (V).

In another preferred embodiment the compound of the present invention isrepresented by Structural Formula (XX):

Ar and Phenyl Ring A in Structural Formula (XX) are as described forStructural Formulas (I) or (VI) and t is an integer from 1 to about 5.

In a more preferred embodiment, R₁ in structural Formula (XX) is para tothe carbon bonded to the alkyne group and is represented by StructuralFormula (II), more preferably by Structural Formulas (III) or (IV) andeven more preferably by Structural Formula (V). Preferably, t is 1, 2 or3.

In another preferred embodiment, the compound of the present inventionis represented by Structural Formula (XXI):

Ar and Phenyl Ring A in Structural Formula (XXI) are as described forStructural Formulas (I) or (VI).

p is zero, one or two.

W₂ is —O—, —C(O)—, —OCH₂—, —CH₂—, —NR₈—, —NR₈CO—, —NR₈CH—, —C(═NOH)— or—CH(NR₇R₈)—. W₂ is preferably —O—.

R₇ and R₈ are independently —H, an aliphatic group, a substitutedaliphatic group, an aromatic group or a substituted aromatic group.

R₁₁ and R₁₂ are independently a C1–C6 alkyl group (preferably C₁–C₃alkyl group), or, taken together are a substituted or unsubstitutedethylene, propylene or butylene group.

In a more preferred embodiment, the compound of the present invention isrepresented by a structural formula selected from Structural Formulas(XXII)–(XXVI):

Ar and Phenyl Ring A in Structural Formulas (XXII)–(XXVI) are asdescribed for Structural Formula (XXI) and R₂ and R₃ in StructuralFormulas (XXII)–(XXVI) are as described in Structural Formula (II). InStructural Formula (XXVI), W₃ is a covalent bond, methylene or ethyleneand R₁₃ and R₁₄ are methyl, ethyl or propyl and are the same ordifferent, preferably the same. Preferably, —CH₂CH(OR₂)COOR₃ inStructural Formulas (XXII)–(XXVI) is represented by Structural Formulas(III) or (IV), more preferably by Structural Formula (V).

In another preferred embodiment the compound of the present invention isrepresented by Structural Formula (XXVII):

Ar, Phenyl Ring A, R₂ and R₃ in Structural Formulas (XXVII) are asdescribed for Structural Formulas (I) or (VI); W₄ and W₅ areindependently methylene or ethylene; and R₁₅ is —H and R₁₆ is a C1–C6alkyl group (preferably methyl ethyl or propyl), or R₁₅ and R₁₆, takentogether, are ═O or ═CH₂. Preferably, —CH₂CH(OR₂)COOR₃ in StructuralFormula (XXVII) is represented by Structural Formulas (III) or (IV),more preferably by Structural Formula (V).

An “aliphatic group” is non-aromatic, consists solely of carbon andhydrogen and may optionally contain one or more units of unsaturation,e.g., double and/or triple bonds. An aliphatic group may be straightchained, branched or cyclic. When straight chained or branched, analiphatic group typically contains between about 1 and about 10 carbonatoms, more typically between about 1 and about 6 carbon atoms. Whencyclic, an aliphatic group typically contains between about 3 and about10 carbon atoms, more typically between about 3 and about 7 carbonatoms. Aliphatic groups are preferably C1–C10 straight chained orbranched alkyl groups (i.e., completely saturated aliphatic groups),more preferably C1–C6 straight chained or branched alkyl groups.Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyland tert-butyl.

A “haloaliphatic group” is an aliphatic group, as defined above,substituted with one or more halogen atoms.

A “haloalkyl group” is an alkyl group (i.e., a saturated aliphaticgroup), as defined above, substituted with one or more halogen atoms.Examples included —CF₃, —CHF₂, —CH₂F, —CF₂CF₃ and the like.

An “aralkyl group” is an alkyl group substituted with an aromatic group,preferably a phenyl group. A preferred aralkyl group is a benzyl group.Suitable aromatic groups are described below and suitable alkyl groupsare described above. Suitable substituents for an aralkyl group aredescribed below.

An “aralkenyl group” is an alkenyl group substituted with an aromaticgroup. An “alkenyl group” is an aliphatic group with one or more carboncarbon double bonds. Suitable aromatic groups are described below.Suitable aliphatic groups are defined above. Suitable substituents foran aralkenyl group are described below.

An “allyl group” has the formula —CH₂CH═CH₂. Suitable substituents foran alkyl group are described below

An “alkylene group” is a polymethylene group, i.e., —(CH₂)_(n)—, whereinn is a positive integer. Preferably, n is an integer from about 2 toabout 10, more preferably from about 2 to about 7. A “substitutedalkylene group” is an alkylene group in which one or more methylenehydrogen atoms are replaced with a substituent. Suitable substituentsare described below.

An “arylene” is an aromatic group in which at least two carbon atoms arebonded to moieties other than hydrogen. Suitable arylene groups arethose corresponding to the aromatic groups described herein.

A “sulfonamide group” is represented by —S(O)₂NH₂. A “substitutedsulfonamide group” is represented by —S(O)₂N(R)₂, wherein each R isindependently —H, C1–C6 alkyl, C1–C6 haloalkyl or aryl-C0–C4-alkyl andat least one R is not —H.

An “acylsulfonamide group” is represented by —S(O)₂NH—C(O)—R wherein Ris —H or a C1–C6 alkyl group or a C1–C6 haloalkyl group. A “substitutedacylsulfonamide group” is represented by —S(O)₂NR′—C(O)R, wherein R is—H or a C1–C6 alkyl group or C1–C6 haloalkyl group and R′ is C1–C6alkyl, C1–C6 haloalkyl or aryl-C0–C4-alkyl.

The term “heteroalkylene group” refers to an alkylene group in which oneor more methylene groups have been replaced by a functional group, e.g.,—(CH₂)_(p)-Z-(CH₂)_(q)— wherein p is a positive integer and q is zero ora positive integer such that p+q is less than 10 and Z is a functionalgroup. Examples of suitable functional groups include —CH═CH—, —C≡C—,—O—, —CO—, —NR₈—, —NR₈CO—, —C(═NOH)—, —S(O)_(k)— and —CH(NR₇R₈)— whereineach R₇ and each R₈ is independently —H, an aliphatic group, asubstituted aliphatic group, an aromatic group or a substituted aromaticgroup; and k is 0, 1 or 2. Preferably, a heteroalkylene group is betweenabout 2 and 10 atoms in length. For purposes of determining the lengthof a heteroalkylene group, in this application a functional group isconsidered to be one atom. Thus, for example, —(CH₂)₃—CO—NH(CH₂)₂— issix atoms in length (five methylene carbons and a functional group); andCH₂)₃—C(═NOH)—(CH₂)₂— is also six atoms in length (five methylenecarbons and an oxime carbon). Examples of preferred heteroalkylenegroups include —(CH₂)₂—O—, —(CH₂)₃—O—, —(CH₂)₄—O—, —CH₂—C≡CH—,—(CH₂)₂—C≡CH—, —(CH₂)₃—C≡CH—, —(CH₂)₄—C≡CH—, —(CH₂)₅—C≡CH—, —(CH₂)CO—,—(CH₂)₂CO—, —(CH₂)₃CO—, —(CH₂)₄CO—, —(CH₂)₂—C(═NOH)—, —(CH₂)₃—C(═NOH)—,—(CH₂)₄—(═NOH)—, —(CH₂)₂—NR₈—, —(CH₂)₃—NR₈—, —(CH₂)₄—NR₈—,—(CH₂)₂—NR₈CO—, —(CH₂)₃—NR₈CO—, —(CH₂)₄—NR₈CO—, —(CH₂)₂—OCH₂—,—(CH₂)₃—OCH₂—, —(CH₂)₄—OCH₂—, —(CH₂)₂—NR₈CH₂—, —(CH₂)₃—NR₈CH₂—,—(CH₂)₄—NR₈CH₂—, —(CH₂)₂CH(NR₇R₈)—, —(CH₂)₃CH(NR₇R₈)— and—(CH₂)₄—CH(NR₇R₈)—.

A “substituted heteroalkylene group” is a heteroalkylene group in whichone or more methylene hydrogen atoms are replaced with a substituent.Preferred substituents include ═O, ═CH₂, C1–C6 alkyl and C2–C4 alkylene.When a heteroalkylene group is substituted with a C2–C4 alkylene group,the C2–C4 alkylene group together with the carbon atoms of theheteroalkylene group to which the two ends of the C2–C4 alkylene groupare bonded and any intervening carbon atoms form a cycloalkyl ring.Structural Formula (XX) provides an example of a heteroalkylene groupsubstituted with a C2–C4 alkylene group, which is represented by R₁₁ andR₁₂ taken together. Specifically, R₁₁ and R_(12,) taken together with—CH—(CH₂)_(p)CH— can form a cycloalkyl ring. Other examples ofheteroalkylene groups substituted by an alkylene are shown in thefollowing structural formulas:

Other suitable substituents for a heteroalkylene group are describedbelow.

A “nonaromatic heterocyclic ring” (or also referred to as a“heterocyclic ring”) is a monocyclic, bicyclic, or tricyclic nonaromaticring of 3 to 14 ring atoms which are saturated or partially saturatedcontaining carbon and from one to four heteroatoms selected from N, O orS. The term “nonaromatic heterocyclic ring” includes nitrogen-containingheterocyclic rings, which contains from one to three nitrogen atoms andoptionally further contains one other heteroatom selected from O or S.Examples include morpholinyl, thiomorphonlyl, pyrrolindinyl, pierazinyl,piperidinyl, azetidinyl, azacycloheptyl, or N-phenylpiperazinyl. Thetern “non-aromatic heterocyclic ring” also includes non-aromaticheterocyclic rings fused to aromatic group, e.g., 1,3-benzodioxole,4-chromanone, and phthalimide. A “non-aromatic heterocyclic ring” may beoptionally substituted with a designated number of substituents, asdescribed below.

An “aromatic group” (also referred to as an “aryl group”) as used hereinincludes carbocyclic aromatic groups, heterocyclic aromatic groups (alsoreferred to as “heteroaryl”) and fused polycyclic aromatic ring systemas defined herein.

A “carbocyclic aromatic group” is an aromatic ring of 5 to 14 carbonsatoms, and includes a carbocyclic aromatic group fused with a 5-or6-membered cycloalkyl group such as indan. Examples of carbocyclicaromatic groups include, but are not limited to, phenyl, 1-naphthyl,2-naphyl, 1-anthracenyl 2-anthracenyl, phenanthrenyl, fluorene,9-fluorenone, indan and the like. A carbocyclic aromatic group isoptionally substituted with a designated number of substituents,described below for aromatic groups.

A “heterocyclic aromatic group” (or “heteroaryl”) is a monocyclic,bicyclic or tricyclic aromatic ring of 5- to 14-ring atoms of carbon andfrom one to four heteroatoms selected from O, N, or S. Examples ofheteroaryl include, but are not limited to N-imidazolyl, 2-imidazole,2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidyl, 4-pyrimidyl 2-pyranyl, 3-pyranyl, 4-pyrazolyl,5-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazoyl,4-oxazoyl, 5-oxazoyl, 2-imidazolyl, isoxazoyl, pyrrolyl, pyrazinyl, andpurinyl and the like. Heterocyclic aromatic (or heteroaryl) as definedabove may be optionally substituted with a designated number ofsubstituents, as described below for aromatic groups.

A “fused polycyclic aromatic” ring system is a carbocyclic aromaticgroup or heteroaryl fused with one or more other heteroaryl ornonaromatic heterocyclic ring. Examples include 2,3-dihydrobenzofuran,dibenzothiophene, dibenzofuran, 2-benzothienyl, 3-benzothienyl,2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl,3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzoimidazolyl,2-qinolinyl, 3-quinolinyl, 1-isoqinolinyl, 3-quinolinyl, 1-isoinoldyl,3-isoindolyl, benzotriazolyl and the like. Fused polycyclic aromaticring systems may optionally be substituted with a designated number ofsubstituents, as described below for aromatic groups.

“Halo” refers to fluoro, chloro, bromo and iodo.

Preferred examples of suitable values for Ar in Structural Formulas (I),and (VI)–(XXVII) are shown below:

Rings B-Z are independently substituted or unsubstituted. Other examplesof suitable groups for Ar include substituted or unsubstitutedbenzoylnaphthyl, thienylphenyl and naphthoylphenyl. Still other examplesof suitable values for Ar are found in Examples 1–379. These aromaticgroups, when used as values for Ar, can be substituted or unsubstituted,as shown in Examples 1–379, or, alternatively, can contain one or moreother aromatic group substituents that are described herein.

X is —O—, —S—, —CH₂— or —C(O).

Z is a covalent bond, —O—, (—CH₂)_(q)—, —CH(CH₃)(CH₂)_(q)—,—C(CH₃)₂(CH₂)_(q)—, —(CH₂)_(q)CH(CH₃)—, —(CH₂)_(q)C(CH₃)₂—,—O(CH₂)_(q)—, —(CH₂)_(q)O—, —(CH₂)_(q)NH—, —(CH₂)_(q)NH—,—(CH₂)_(q)CHR₂₀—, —CHR₂₀(CH₂)_(q)—, —(CH₂)_(q)CR₂₀R₂₀—,—(CH₂)_(q)CR₂₀R₂₀—, —(CH₂)_(q)NR₂₀—, —NR₂₀(CH₂)_(q)—,—(CH₂)_(q)C(═NOH)—, —C(═NOH)(CH₂)_(q)—, —CH(OH)—(CH₂)_(q)—,—(CH₂)_(q)—CH(OH)—, —CO—(CH₂q—, —(CH₂)_(q)—CO—, —COO—(CH₂)_(q)—,—OCO—(CH₂)_(q)—, —(CH₂)_(q)—OCO—, —(CH₂)_(q)—COO—, —(CH₂)_(q)CO—NH—,—(CH₂)_(q)NH—CO—, —(CH₂)_(q)CONR₂₀—, —CONR₂₀(CH₂)_(q)—,—(CH₂)_(q)NR₂₀CO— or —NR₂₀CO(CH₂)_(q)—. Z is preferably a covalent bond,—C(═NOH), —O— or —C(O)— (more preferably —O— or —C(O)—); and q is 0, 1,2 or 3, preferably 0 or 1.

Each R₂₀ is independently a C1–C5 alkyl group or halogenated C1–C5 alkylgroup.

Especially preferred values groups for Ar in Structural Formulas (I) and(VI)–(XXVII) are shown below:

Phenyl Rings A′ and A″ are substituted or unsubstituted.

Suitable substituents for an aromatic group, including the aromaticgroup represented by Ar (e.g., Phenyl Rings A′ and A″ and Rings B-Z) andPhenyl Ring A, an aliphatic group, an alkyl group, an alkylene group, aheteroalkylene group, a non-aromatic heterocyclic group, an aralkylgroup, an aralkenyl group and an alkyl group are those which do notsignificantly diminish the activity of the compound at the PeroxisomeProliferator Activated Receptors (PPARs), e.g., decrease the activity bymore than a factor of five (preferably no more than a factor of two)compared with the corresponding compound without the substituentExamples of substituents include halogen (—Br, —Cl, —I and —F) —R, —OR,—CN, —NO₂, —N(R)₂, —COR, —COOR, —CON(R)₂, —SO_(k)R (k is 0, 1 or 2) and—NH—C(═NH)—NH₂. Other examples include sulfonamide, acylsulfonamide,—NR—CO—R, —OS(O)R, —OS(O)₂R, cycloalkyl groups, substituted orunsubstituted non-aromatic heterocyclic groups, —O(CH₂)_(r)COOH—O—O(CH₂)_(r)—N(R)₂, —O(CH₂)_(r)-(cycloalkyl), —O(CH₂)_(r)OH,—O(CH₂)_(r)—OSi(R)₃, and —(CH₂)_(a)CH(OR₃₀)(CH₂)_(b)COOR₃₁. Each R isindependently —H, an aliphatic group, a substituted aliphatic group, ahalogenated aliphatic group, a benzyl group, a substituted benzyl group,an aromatic group or a substituted aromatic group, and preferably —H, analkyl group (e.g., a C1–C10 alkyl group), a halogenated alkyl group(e.g., a C1–C10 halogenated alkyl group), a phenyl group or asubstituted phenyl group; R₃₀ is a C1–C6 alkyl group or C1–C6halogenated alkyl group, R₃₁ is —H, a C1–C6 alkyl group or C1–C6halogenated alkyl group; r is an integer from 1 to 6; a and b areindependently 0, 1 or 2. An aromatic group, benzylic group, an aliphaticgroup, an alkyl group, an alkylene group, a heteroalkylene group, anon-aromatic heterocyclic group, aralkyl group and aralkenyl group canhave more than one substituent. Other examples of suitable substituentsfor an aromatic group represented by Ar are those found at thecorresponding position of the compounds descried in the ExemplificationSection.

Preferred substituents for Rings B-Z include halogen, —R₉, —OR₉, —COR₉,—COOR₉, —CN, a non-aromatic heterocyclic group, an allylic group,—(CH₂)_(a)CH(OR₃₀)(CH₂)_(b)COOR₃₁ or —NR₉C(O)R₉. R₉ is —H, an alkylgroup (e.g., a C1–C10 alkyl group), cycloalkyl, a halogenated alkylgroup (e.g., a C1–C10 halogenated alkyl group) or an aromatic group.R₃₀, R₃₁, a and b are as described above; preferably R₃₀ is methyl orethyl, R₃₁ is —H₃ and a and b are one.

More preferably, suitable substituents for Rings B-Z include one or moregroups selected from halogen, C1–C8 straight chained or branched alkyl,C1–C8 straight chained or branched halogenated alkyl (e.g., —CF₃), C3–C8cycloalkyl, C1–C8 straight chained or branched alkanoyl, C1–C8 straightchained or branched alkoxy (e.g., methoxy), —Br, —F, N-morpholino,—COOH, —OH, —CN, or C1–C8 straight chained or branched halogenatedalkoxy (e.g., —OCF₃).

Suitable substituents for Phenyl Rings A′ and A″ are as described abovefor Rings B-Z.

Preferred substituents for Phenyl Ring A include halogen, —OR₁₀, —R₁₀,aromatic group, substituted aromatic group, aralkyl, substitutedaralkyl, aralkenyl, substituted aralkenyl, allyl and substituted allyland R₁₀ is —H, an alkyl group (e.g., a C1–C10 all group) or ahalogenated alkyl group (e.g., a C1–C10 halogenated alkyl group).Specific examples of suitable substituents for Phenyl Ring A include —F,—Cl, —OCH₃, —OCF₃, —CH₃, ethyl, n-propyl, iso-propyl, alkyl,2-phenylethenyl, 2-phenylethyl, phenyl, -o-biphenyl, -m-biphenyl,-p-biphenyl, -o-C₆H₄OCH₃, -m-C₆H₄OCH₃, -p-C₆H₄OCH₃, -o-C₆H₄F, -m-C₆H₄Fand -p-C₆H₄F.

Another embodiment of the present invention is a compound represented byStructural Formula (XLII):

Ar and R₁ in Structural Formula (XLI) are as defined above in StructuralFormulas (I) and (VI); s is 0, 1 or 2; Ar₁ is a substituted orunsubstituted arylene group; W₆ is a covalent bond, —W₁—, —CH₂W₁— or—W₁CH₂—; W₇ is a covalent bond or —CH₂— and W₁ is as defined above.Preferably R₁ is represented by Structural Formula (II), s is 0 or 1,Ar₁ is phenylene (ortho, meta or para substituted), W₇ is a covalentbond and W₁ is —O—. More preferably, Ar is represented by any one ofStructural Formulas (XXVIII)–(XXXIX) and R₁ is represented by StructuralFormulas (III) or (IV). Even more preferably, Ar is represented byStructural Formulas (XL) or (XLI) and R₁ is represented by StructuralFormula (V).

Also included in the present invention are methods of treatment asdescribed above, wherein the compound represented by Structural Formula(XLI) is administered as the therapeutic agent and the use of thecompound for the manufacture of a medicament for the treatment of thePPAR mediated disorders described herein.

The following are specific examples of the compounds of the presentinvention:

-   (2S)-3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 1);-   (2S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 2);-   (2S)-2-Methoxy-3-{4-[3-phenoxy-phenoxy)-prop-1-ynyl]-phenyl}-propionic    acid (Compound 3);-   (2S)-3-{4-[3-(4-Fluoro-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 4);-   (2S)-2-Methoxy-3-{4-[3-(3-phenyl-benzofuran-6-yloxy)-prop-1-ynyl]-phenyl}-propionic    acid (Compound 5);-   (2S)-3-{4-[3-(4-Butyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 6);-   (2S)-2-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-prop-1-ynyl}-phenyl)-propionic    acid (Compound 7);-   (2S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy)-prop-1-ynyl]-phenyl}-propionic    acid (Compound 8);-   (2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-prop-1-ynyl]-phenyl}-propionic    acid (Compound 9);-   (2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 10);-   (2S)-2-Methoxy-3-{4-[3-(3-phenylamino-phenoxy)-prop-1-ynyl]-phenyl}-propionic    acid (Compound 11);-   (2S)-3-({3-[4-(4-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 12);-   (2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-prop-1-ynyl]-phenyl}-propionic    acid (Compound 13);-   (2S)-3-(4-{3-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 14);-   (2S)-2-Methoxy-3-(4-{3-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-prop-1-ynyl}-phenyl)-propionic    acid (Compound 15);-   (2S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-prop-1-ynyl]-phenyl}-propionic    acid (Compound 16);-   (2S)-3-{4-[3-(4-Benzyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 17);-   (2S)-3-[4-(3-{4-[(2-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-prop-1-ynyl)-phenyl]-2-methoxy-propionic    acid (Compound 18);-   (2S)-3-(4-{3-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 19);-   (2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-prop-1-ynyl)-phenyl]-2-methoxy-propionic    acid (Compound 20);-   (2S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 21);-   (2S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionic    acid (Compound 22),-   (2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 23);-   (2S)-3-{4-[5-(4-Benzyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 24);-   (2S)-3-(4-{5-[4-(4-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 25);-   (2S)-2-Methoxy-3-(4-{5-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-pent-1-ynyl}-phenyl)-propionic    acid (Compound 26);-   (2S)-2-Methoxy-3-{4-[5-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-pent-1-ynyl]-phenyl}-propionic    acid (Compound 27);-   (2S)-2-Methoxy-3-{4-[5-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-pent-1-ynyl]-phenyl}-propionic    acid (Compound 28);-   (2S)-2-Methoxy-3-(4-{5-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-pent-1-ynyl}-phenyl)-propionic    acid (Compound 29);-   (2S)-2-Methoxy-3-{4-[5-(9-oxo-9H-fluoren-2-yloxy)-pent-1-ynyl]-phenyl}-propionic    acid (Compound 30);-   (2S)-2-Methoxy-3-{4-[5-3-phenylamino-phenoxy)-pent-1-ynyl]-phenyl}-propionic    acid (Compound 31);-   (2S)-3-(4-{5-[4-(2-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 32);-   (2S)-2-Methoxy-3-{4-[5-(3-phenyl-benzofuran-6-yloxy)-pent-1-ynyl]-phenyl}-propionic    acid (Compound 33);-   (2S)-3-(4-{5-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 34);-   (2S)-2-Methoxy-3-{4-[5-(4-phenylacetyl-phenoxy)-pent-1-ynyl]-phenyl}-propionic    acid (Compound 35);-   (2S)-3-{4-[5-(4-Butyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 36);-   (2S)-3-[4-(5-{4-[(2-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pent-1-ynyl)-phenyl]-2-methoxy-propionic    (Compound 37);-   (2S)-3-[4-(5-{4-[(4-Fluoro-Phenyl)-hydroxyimino-methyl]-phenoxy}-pent-1-ynyl)-phenyl]-2-methoxy-propionic    acid (Compound 38);-   (2S)-3-(4-{5-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 39);-   (2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 40);-   (2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-1-ynyl]-phenyl}-propionic    acid (Compound 41);-   (2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 42);-   (2S)-3-(4-{4-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-but-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 43);-   (2S)-3-(4-{4-[4-Fluoro-benzoyl)-phenoxy]-but-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 44);-   (2S)-3-(4-{4-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-but-1-ynyl}-phenyl)-2-methoxy-propionic    acid (Compound 45);-   (2S)-2-Methoxy-3-(4-{4-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-but-1-ynyl}-phenyl)-propionic    acid (Compound 46);-   (2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-but-1-ynyl]-phenyl}-propionic    acid (Compound 47);-   (2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-but-1-ynyl]-phenyl}-propionic    acid (Compound 48);-   (2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hex-1-ynyl]-phenyl}-propionic    acid (Compound 49);-   (2S)-3-{4-[6-(4-Benzoyl-phenoxy)-hex-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 50);-   (2S)-3-{4-[6-(Biphenyl-4-yloxy)-hex-1-ynyl]-phenyl}-2-methoxy-propionic    acid (Compound 51);-   (2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propionic    acid (Compound 52);-   (2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pentanoyl]-phenyl}-2-methoxy-propionic    acid (Compound 53);-   (2S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pentanoyl]-phenyl}-propionic    acid (Compound 54);-   3-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionic    acid (Compound 55);-   (2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butyryl]-phenyl}-propionic    acid (Compound 56);-   (2S)-3-[4-(Biphenyl-4-yloxy)-butyryl-phenyl]-2-methoxy-propionic    acid (Compound 57);-   (2S)-3-{4-[6-(Biphenyl-4-yloxy)-hexanoyl]-phenyl}-2-methoxy-propionic    acid (Compound 58);-   (2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hexanoyl]-phenyl}-propionic    acid (Compound 59);-   (2S)-3-{4-[6-(4-Benzoyl-phenoxy)-hexanoyl]-phenyl}-2-methoxy-propionic    acid (Compound 60);-   (2S)-3-{4-[5-(Biphenyl-4-yloxy)-1-hydroxyimino-pentyl]-phenyl}-2-methoxy-propionic    acid (Compound 61);-   (2S,1′R*,2′S*)-3-(4-{2′-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclopentyloxy}-phenyl)-2-methoxy-propionic    acid (Compound 62);-   (2S)-(1′R,3′R)-2-Methoxy-3-{4-[1′,3′-dimethyl-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionic    acid (Compound 63);-   (2S)-(1′R,3′R)-3-{4-[3-(4-Benzoylphenoxy)-1′,3′-dimethylpropoxyl]-phenyl}2-methoxy-propionic    acid (Compound 64);-   (2S)-(1′S,3′S)-2-Methoxy-3-{4-[1′,3′-dimethyl-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionic    acid (Compound 65);-   (2S)-(1′S,3′S)-3-{4-[3-(4-Benzoylphenoxy)-1′,3′-dimethylpropoxyl]-phenyl}2-methoxy-propionic    acid (Compound 66);-   (2S)-(1′R,2′R)-2-Methoxy-3-{4-[1′,2′-dimethyl-(4-phenoxy-phenoxy)-ethoxyl]-phenyl}-propionic    acid (Compound 67);-   (2S)-(1′R,2′R)-3-{4-[1-(4-Benzoylphenoxy)-1′,2′-dimethyl-ethoxyl]-phenyl}-2-methoxypropionic    acid (Compound 68);-   (2S)-(1′S,4′S)-2-Methoxy-3-{4-[1′-methyl-4′-(4-phenoxy-phenoxy)-pentyloxy]-phenyl}-propionic    acid (Compound 69);-   (2S)-(1′S,4′S)-3-{4-[4-(4-Benzoyl-phenoxy)-1-methyl-pentyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 70);-   (2S)-(1′R,4′R)-2-Methoxy-3-{4-[1′-methyl-4′-(4-phenoxy-phenoxy)-pentyloxy]-phenyl}-propionic    acid (Compound 71);-   (2S)-(1′R,4′R)-3-{4-[4-(4-Benzoyl-phenoxy)-1-methyl-pentyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 72);-   (2S)-(1′S,2′S)-2-Methoxy-3-{4-[1′,2′-dimethyl-(4-phenoxy-phenoxy)-ethoxyl]-phenyl}-propionic    acid (Compound 73);-   (2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionic    acid (Compound 74);-   (2S)-2-Methoxy-{4-[2-oxo-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionic    acid (Compound 75);-   (2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxymethyl)-benzyloxy]-phenyl}-propionic    acid (Compound 76);-   (2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxymethyl)-benzyloxy]-phenyl}-propionic    acid (Compound 77);-   (2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-phenoxy]-phenyl}-propionic    acid (Compound 78),-   (2S)3-[3′-(3-Benzoyl-phenoxymethyl)biphenyl-4-yl]-2-methoxy-propionic    acid (Compound 79);-   (2S)-3-[4′-(4-Benzoyl-phenoxymethyl)-biphenyl-4-yl-2-methoxy-propionic    acid (Compound 80);-   (2S)-(1′R*,3′R*)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 81);-   (2S)-(1′R*,3′S*)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 82);-   (2S)-(1′R*,3′R*)-2-Methoxy-3-{4-[3′-(4-phenoxy-phenoxy)-1′-cyclopentyloxy]-phenyl}-propionic    acid (Compound 83);-   (2S)-(1′R*,3′R*)-3-{4-[3-(4-Benzoyl-phenoxy)-cyclopentyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 84);-   (2S)-(1′R*,3′R*)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-cyclopentyloxy]-phenyl}-propionic    acid (Compound 85);-   (2S)-(1′R,3′S)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 86);-   (2S)-(1′S,3′R)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 87);-   (2S)-(1′S,3′S)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 88);-   (2S)-(1′R,3′R)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 89);-   (2S)-(1′R,3's)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 90);-   (2S)-(1′S,3′R)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 91);-   (2S)-(1′R,3′R)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclphenyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 92);-   (2S)-(1′S,3′S)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 93);-   (2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 94);-   (2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 95);-   (2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 96);-   (2S)-2-Methoxy-3-{4-[3-(3-phenylamino-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 97);-   (2S)-3-{4-[3-Butyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 98);-   (2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 99);-   (2S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 100);-   (2S)-2-Methoxy-3-{4-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 101);-   (2S)-2-Methoxy-3-{4-[3-(3-morpholinyl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 102);-   (2S)-3-{4-[3-(Biphenyl-2-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 103);-   (2S)-3-{4-[3-(4-Cylopentyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 104);-   (2S)-3-{4-[3-(4-Cyano-3-fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 105);-   (2S)-3-{4-[3-(2,4-Difluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 106);-   (2S)-2-Methoxy-3-{4-[3-(4-trifluoromethyl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 107);-   (2S)-2-Methoxy-3-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 108);-   (2S)-2-Methoxy-3-{4-[3-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 109);-   (2S)-3-{4-[3-(3,5-Difluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 110);-   (2S)-3-{4-[3-(Isoquinolin-5-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 111);-   (2S)-2-Methoxy-3-{4-[3-(4-trifluoromethoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 112);-   (2S)-3-{4-[3-(4-Fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 113);-   (2S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 114);-   (2S)-2-Methoxy-3-(4-{3-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 115);-   (2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 116);-   4-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid    benzyl ester (Compound 117);-   (2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-6-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 118);-   (2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-6-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 119);-   (2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-7-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 120);-   (2S)-2-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 121);-   (2S)-3-{4-[2-(4-benzoyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 122);-   (2S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 123);-   (2S)-3-{4-[2-(Biphenyl-4-yloxy)-acetyl]-phenyl}-2-methoxy-propionic    acid (Compound 124);-   (2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxy)-acetyl]-phenyl}-propionic    acid (Compound 125);-   (2S)-3-{4-[2-(4-Benzoyl-phenoxy)-acetyl]-phenyl}-2-methoxy-propionic    acid (Compound 126);-   (2S)-3-{4-[3-(Biphenyl-4-yloxy)-propyl]-phenyl}-2-methoxy-propionic    acid (Compound 127);-   (2S)-3-{4-[4-(Biphenyl-4-yloxy)-butyl]-phenyl}-2-methoxy-propionic    acid (Compound 128);-   (2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentyl]-phenyl}-2-methoxy-propionic    acid (Compound 129);-   3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methoxy-propionic acid    (Compound 130);-   3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-3-methoxy-phenyl)-2-methoxy-propionic    acid (Compound 131);-   3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionic    acid (Compound 132);-   2-Methoxy-3-{3-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 133);-   (2S)-3-(4-[3-phenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionic    acid (Compound 134);-   3-{3-Chloro-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 135);-   ′3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionic    acid (Compound 136);-   3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3,5-dichloro-6-phenyl}-2-methoxy-propionic    acid (Compound 137);-   3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-propionic    acid (Compound 138);-   3-{4-[3-(3-(Biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2-methoxy-propionic    acid (Compound 139);-   (2S)-3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4′-methoxy-biphenyl-3-yl}-2-methoxy-propionic    acid (Compound 140);-   3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4′-fluoro-biphenyl-3-yl}-2-methoxy-propionic    acid (Compound 141);-   3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-[1,1′;4′,1″]terphenyl-3-yl}-2-methoxy-propionic    acid (Compound 142);-   3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-2′-methoxy-biphenyl-3-yl}-2-methoxy-propionic    acid (Compound 143);-   2-Methoxy-3-{6-[3-(4-phenoxy-phenoxy)-propoxy]-[1,1′;4′,1″]terphenyl-3-yl}-propionic    acid (Compound 144);-   3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-styryl-phenyl}-2-methoxy-propionic    acid (Compound 145);-   3-(4-{3-[4-(Hydroxy-phenyl-methyl)-phenoxy]-propoxy}-3-phenethyl-phenyl)-2-methoxy-propionic    acid (Compound 146);-   3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-3-phenethyl-phenyl}-2-methoxy-propionic    acid (Compound 147);-   (2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 148);-   (2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-3-propyl-phenyl}-propionic    acid (Compound 149);-   3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acrylic    acid (Compound 150);-   3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-propionic    acid (Compound 151),-   3-{3-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (Compound 152);-   ′2-Methoxy-3-{3-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 153);-   3-{3-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 154);-   2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionic    acid (Compound 155);-   2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pentyl]-phenyl}-propionic acid    (Compound 156);-   2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pentanoyl]-phenyl}-propionic    acid (Compound 157);-   3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 158);-   (2S)-2-Methoxy-3-{4-[3-(3-propyl-biphenyl-4-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 159);-   (2S)-3-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 160);-   (2S)-2-Methoxy-3-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 161);-   3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propionic    acid (Compound 162);-   2-Methoxy-3-{3-methyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 163);-   3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propionic    acid (Compound 164);-   (2S)-3-{4-[3-(Dibenzofuran-2-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 165);-   (2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionic    acid (Compound 166);-   (2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxy-methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionic    acid (Compound 167);-   (2S)-2-Methoxy-3-(4-{3-[4-(4-piperidin-1-yl-benzoyl)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 168);-   (2S)-2-Methoxy-3-(4-{3-[4-(4-morpholin-4-yl-benzoyl)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 169);-   (2S)-3-(4-{3-[4-(4-Hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 170);-   (2S)-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoic    acid sodium salt (Compound 171);-   (2S)-3-[4-(3-{4-[Hydroxyimino-(4-hydroxy-phenyl)-methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionic    acid (Compound 172);-   (2S)-3-{4-[3-(4-Benzoyl-3-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 173);-   (2S)-3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 174);-   3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionic    acid (Compound 175);-   (S)-3-(4-benzyloxy-phenyl)-2-isopropoxy-propionic acid (Compound    176);-   (2S)-2-isopropoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoic    acid sodium salt (Compound 176A);-   2-Methoxy-3-{3-methoxy-4-[3-(4-phenylacetyl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 177);-   3-{4-[3-(4-Butoxy-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionic    acid (Compound 178);-   2-Methoxy-3-{3-methoxy-4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 179);-   2-Methoxy-3-(3-methoxy-4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 180);-   3-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionic    acid (Compound 181);-   3-{4-[3-(4-Dibenzofuran-3-yl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionic    acid (Compound 182);-   (2S)-3-{4-[4-(Biphenyl-4-yloxy)-butoxy]-phenyl}-2-methoxy-propionic    acid (Compound 183);-   (2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propionic    acid (Compound 184);-   (2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propionic    acid (Compound 185);-   (2S)-2-Methoxy-3-{4-[2-(2,3,6-trifluoro-phenoxy)-ethoxy]-phenyl}-propionic    acid (Compound 186);-   (2S)-3-[4-(3-Benzyloxy-benzyloxy)-phenyl]-2-methoxy-propionic acid    (Compound 187);-   3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-propionic    acid (Compound 188);-   3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-propionic    acid (Compound 189);-   2-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 190);-   3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionic    acid (Compound 191);-   3-{2-Chloro-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 192);-   3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionic    acid (Compound 193);-   (2S)-4-{3-[4-(2-Carboxy-2-methoxy-ethyl-phenoxy]-propoxy}-benzoic    acid (Compound 194);-   (2S)-3-{4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 195);-   (2S)-3-{4-[3-(4′-Hydroxy-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 196);-   (2S)-4′-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylic    acid (Compound 197);-   (2S)-3-{4-[2-(4-Benzoyl-phenoxy)-cyclohexyloxy]-phenyl}-2-methoxy-propionic    acid (Compound 198);-   (2S)-3-(4-{2-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclohexyloxy}-phenyl)-2-methoxy-propionic    acid (Compound 199);-   (2S)-3-(4-{3-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 200);-   (2S)-2-Methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 201);-   (2S)-3-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 202);-   (2S)-3-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 203);-   (2S)-3-{4-[3-(4-Heptyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 204);-   (2S)-3-{4-[3-(6-Benzoyl-naphthalen-2    yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid (Compound 205);-   (2S)-3-{4-[3-(Benzo[1,3]dioxol-5-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 206);-   (2S)-3-{4-[3-(9H-Fluoren-2-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 207);-   (2S)-2-Methoxy-3-{4-[3-(4-octyl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 208);-   (2S)-2-Methoxy-3-{4-[3-(naphthalen-1-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 209);-   (2S)-3-{4-[3-(1H-Indol-7-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 210);-   (2S)-3-{4-[3-(4′-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 211);-   (2S)-3-{4-[3-(4′-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 212);-   (2S)-3-{4-[3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 213);-   (2S)-3-{4-[3-(4-Dibenzofuran-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 214);-   (2S)-2-Methoxy-3-{4-[3-(4′-phenoxy-biphenyl-4-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 215);-   (2S)-2-Methoxy-3-{4-[3-(4-thiophen-2-yl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 216);-   (2S)-3-{4-[3-(3′-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 217);-   (2S)-3-{4-[3-(2′-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 218);-   (2S)-3-{4-[3-(2′-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 219);-   (2S)-3-{4-[3-(4-Benzo[1,3]dioxol-5-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 220);-   (2S)-3-{4-[3-(4′-tert-Butyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 221);-   (2S)-2-Methoxy-3-{4-[3-(3′-trifluoromethoxy-biphenyl-4-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 222);-   (2S)-2-Methoxy-3-{4-[3-(4′-trifluoromethoxy-biphenyl-4-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 223);-   (2S)-3-(4-{3-[4-(2-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 224);-   (2S)-2-Methoxy-3-(4-{3-[4-(2-methoxy-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 225);-   (2S)-3-(4-{3-[4-(2,2-Dimethyl-propionylamino)-phenoxy)-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 226);-   (2S)-3-(4-{3-[4-(3-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 227);-   (2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 228);-   (2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 229);-   (2S)-3-(4-{3-[4-(4-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 230);-   (2)-3-(4-{3-[4-(4-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 231);-   (2S)-2-Methoxy-3-(4-{3-[4-(4-methoxy-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 232);-   (2S)-2-Methoxy-3-{4-[3-(4-phenylacetylamino-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 233);-   (2S)-3-(4-{3-[4-(2-Chloro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 234);-   (2S)-2-Methoxy-3-(4-{3-[4-naphthalene-1-carbonyl)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 235);-   (2S)-3-(4-{3-[4-(3-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 236);-   (2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 237);-   (2S)-2-Methoxy-3-(4-{3-[4-(naphthalene-2-carbonyl)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 238);-   (2S)-2-Methoxy-3-(4-{3-[4-(4-methyl-benzoyl)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 239);-   (2S)-3-(4-{3-[4-(2,2-Dimethyl-propionyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 240);-   (2S)-3-{4-[3-(4-Isobutyryl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 241);-   (2S)-2-Methoxy-3-(4-{3-[4-(3-phenyl-propionyl)-phenoxy-]propoxy}-phenyl)-propionic    acid (Compound 242);-   3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionic    acid (Compound 243);-   2-phenoxy-3-[4-(4-phenoxy-phenoxy)propoxyphenyl]propanoic acid    (Compound 244);-   (2S,2′S)-3-(4-{3-[4-(2′-Carboxy-2′-methoxy-ethyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 245);-   α-Methoxycinnamate Intermediate, ethyl    (2S)-2-methoxy-3-(4-hydroxyphenyl) propanoate (Compound 246);-   (2S)-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoic    acid (Compound 247);-   (2S)-(2′RS)-2-Methoxy-{4-[2′-methyl-3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 248);-   2(S)-3-[4-(3-Benzyloxy-propoxy)-phenyl]-2-methoxypropionic acid    (Compound 249);-   (2S)-3-[4-(5-Benzyloxy-pentyloxy)-phenyl]-2-methoxypropionic acid    (Compound 250);-   (2S)-2-ethoxy-{4-[3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionic    acid (Compound 251);-   (2S)-2-Benzyloxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 252);-   (2S)-3-{4-[3-(4-{4-[2-(tert-Butyl    dimethyl-silanyloxy)-ethoxy]-benzoyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 253);-   (2S)-3-[4-(3-{4-[4-(2-Hydroxy-ethoxy)-benzoyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionic    acid (Compound 254);-   (2S)-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propionic    acid (Compound 255);-   (2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic    acid (Compound 256);-   (2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic    acid (Compound 257);-   (2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionic    acid (Compound 258);-   (2S)-4′-{3-[4-(2-Carboxy-2-methoxy-ethyl)-2-methoxy-phenoxy]-propoxy}-biphenyl-4-carboxylic    acid (Compound 259);-   (2S)-3-{4-[3-(4′-tert-Butyl-biphenyl-4-yloxy)-propoxy]-2-methoxy-propionic    acid (Compound 260);-   (2S)-3-(4-{3-[4-(4-Hydroxy-phenoxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 261);-   (2S)-2-Methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 262);-   (2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-butoxy)-phenoxy]-propoxy}-phenyl)-propionic    acid (Compound 263);-   (2S)-3-3-{4-[3-(4-Isobutoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 264);-   (2S)-3-{4-[3-(4-Isopropoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 265);-   (2S)-3-{4-[3-(4-Cyclohexylmethoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 266);-   (2S)-2-Methoxy-3-{4-[3-(4-phenetyloxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 267);-   (2S)-3-(4-{3-[4-(3-Dimethylamino-propoxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 268);-   (2S)-3-{4-[3-(4-Carboxymethoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 269);-   (2S)-3-(4-{3-[4-(1H-Indol-5-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 270);-   (2S)-Methoxy-3-{4-[3-(4-pyridin-3-yl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 271);-   (2S)-2-Methoxy-3-{4-[3-(4-pyridin-4-yl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 272);-   (2S)-2-Methoxy-3-{4-[3-(4-quinolin-8-yl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 273);-   (2S)-3-{4-[3-(4′-Cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 274);-   (2S)-2-Methoxy-3-(4-{3-[4)-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-propoxy}-phenyl)-propionic    acid (Compound 275);-   (2)-3-{4-[3-(4-Imidazol-1-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 276);-   (2S)-3-(4-{3-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 277);-   (2S)-3-(4-{3-[4-(4-Acetyl-piperazin-1-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionic    acid (Compound 278);-   (2S)-2-Methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 279);-   (2S)-2-Methoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 280);-   (2S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionic    acid (Compound 281);-   3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionic    acid (Compound 282);-   (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 283);-   (2S)-2-methoxy-3-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 284);-   (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid    (Compound 285);-   (2S)-3-{4-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 286);-   (2S)-2-methoxy-3-{4-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}-propionic    (Compound 287);-   (2S)-2-methoxy-3-{4-[3-(3-morpholin-4-yl-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 288);-   (2S)-2-methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 289);-   2-methoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic acid    (Compound 290);-   3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (isomer 1) (Compound 291);-   3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (Isomer 2) (Compound 292);-   (2S)-3-{4-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 293);-   (2S)-2-methoxy-3-{4-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 294);-   (2S)-2-{3-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic    acid (Compound 295);-   (2S)-3-{4-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 296);-   (2S)-3-{4-[3-(3-dimethylamino-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 297);-   (2S)-3-{3-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic    acid (Compound 298);-   (2S)-3-{4-[3-(indan-5-yloxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 299);-   (2S)-2-methoxy-3-{4-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 300);-   (2S)-3-{4-[3-(1H-indol-5-yloxy)-propoxy]phenyl}-2-methoxy-propionic    acid (Compound 301);-   (2S)-2-methoxy-3-{4-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionic    acid (Compound 302);-   (2S)-2-methoxy-3-{4-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (Compound 303);-   (2S)-3-{4-[3-(3-fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 304);-   (2S)-3-{4-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (Compound 305);-   (2S)-2-methoxy-3-[4-(2-phenoxy-ethoxy)-phenyl]-propionic acid    (Compound 306);-   (2S)-3-{4-[2-(2-cyano-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 307);-   (2S)-2-methoxy-3-{4-[2-(2-methoxy-phenoxy)-ethoxy]-phenyl}-propionic    acid (Compound 308);-   (2S)-3-{4-[2-(biphenyl-2-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 309);-   (2S)-2-{2-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-ethoxy}-benzoic    acid (Compound 310);-   (2S)-3-{4-[2-(2-isopropyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 311);-   (2S)-3-{4-[2-(3-cyano-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 312);-   (2S)-3-{4-[2-(3-dimethylamino-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    (Compound 313);-   (2S)-3-{4-[2-(biphenyl-3-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 314);-   (2S)-3-{2-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-ethoxy}-benzoic    acid (Compound 315);-   (2S)-3-{4-[2-(indan-5-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 316);-   (2S)-2-methoxy-3-{4-[2-(naphthalen-2-yloxy)-ethoxy]-phenyl}-propionic    acid (Compound 317);-   (2S)-2-Methoxy-3-{4-[2-(quinolin-6-yloxy)-ethoxy]-phenyl}-propionic    acid (Compound 318);-   (2S)-2-Methoxy-3-{4-[2-(3-morpholin-4-yl-phenoxy)-ethoxy]-phenyl}-propionic    acid (Compound 319);-   (2S)-2-methoxy-3-{4-[2-(2-methyl-benzothiazol-5-yloxy)-ethoxy]-phenyl}-propionic    (Compound 320);-   (2S)-2-methoxy-3-{4-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propionic    acid (Compound 321);-   (2S)-3-{4-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 322);-   2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propionic acid (isomer 1)    (Compound 323);-   3-{3-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (isomer 1) (Compound 324);-   3-{3-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (isomer 1) (Compound 325);-   2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propionic acid (isomer 2)    (Compound 326);-   3-{3-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (isomer 2) (Compound 327);-   3-{3-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (isomer 2) (Compound 328);-   2-methoxy-3-{3-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (isomer 1) (Compound 329);-   2-methoxy-3-{3-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (isomer 2) (Compound 330);-   3-{3-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxypropionic    acid (isomer 1) (Compound 331);-   3-{3-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (isomer 2) (Compound 332);-   3-{3-[3-(2-carboxy-2-methoxy-etyl)-phenoxy]-propoxy}-benzoic acid    (isomer 1) (Compound 333);-   3-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid    (isomer 2) (Compound 334);-   2-methoxy-3-{3-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (isomer 1) (Compound 335);-   2-methoxy-3-{3-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionic    acid (isomer 2) (Compound 336);-   2-methoxy-3-{3-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propionic    acid (isomer 1) (Compound 337);-   2-methoxy-3-{3-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propionic    acid (isomer 2) (Compound 338);-   2-methoxy-3-{3-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}-propionic    acid (isomer 1) (Compound 339);-   2-methoxy-3-{3-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}-propionic    acid (isomer 2) (Compound 340);-   3-{3-]3-(2-chloro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (isomer 1) (Compound 341);-   3-{3-[3-(2-chloro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (isomer 2) (Compound 342);-   3-{3-[3-(3,4-dimethyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (isomer 1) (Compound 343);-   3-{3-[3-(3,4-dimethyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic    acid (isomer 2) (Compound 344);-   2-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid    (isomer 1) (Compound 345);-   3-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid    (isomer 2) (Compound 346);-   3-{3-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid    isomer 1) (Compound 347);    3-{3-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid    (isomer 2) (Compound 348);-   2-methoxy-3-{3-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionic acid    (isomer 1) (Compound 349);-   2-methoxy-3-{3-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionic acid    (isomer 2) (Compound 350);-   3-{3-[2-(2-isopropyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (isomer 2) (Compound 351);-   2-methoxy-3-{3-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propionic acid    (isomer 1) (Compound 352);-   3-{3-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid    (isomer 1) (Compound 353);-   2-methoxy-3-{3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethoxy]-phenyl}-propionic    acid (isomer 1) (Compound 354);-   2-methoxy-3-{3-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propionic acid    (isomer 2) (Compound 355);-   3-{3-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid    (isomer 2) (Compound 356);-   2-methoxy-3-{3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethoxy]-phenyl}-propionic    acid (isomer 2) (Compound 357);-   (2S)-2-methoxy-3-{4-[2-(4-trifluoromethyl-phenoxy)-ethoxy]-phenyl}-propionic    acid (Compound 358);-   (2S)-2-methoxy-3-(4-{2-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-ethoxy}-phenyl)-propionic    acid (Compound 359);-   (2S)-3-{4-[2-(4-benzyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 360);-   (2S)-2-methoxy-3-{4-[2-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-ethoxy]-phenyl}-propionic    acid (Compound 361);-   (2S)-3-{4-[2-(4-cyclopentyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 362);-   (2S)-3-{4-[2-(9H-fluoren-2-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 363);-   (2S)-3-{4-[2-(4-butyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 364);-   (2S)-3-{4-[2-(2′-fluoro-biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 365);-   (2S)-3-(4-{2-[4-(2,2-dimethyl-propionyl)-phenoxy]-ethoxy}-phenyl)-2-methoxy-propionic    acid (Compound 366);-   3-(4-{2-[4-(2,2-dimethyl-propionylamino)-phenoxy]-ethoxy}-phenyl)-2-methoxy-propionic    acid (Compound 367);-   (2S)-3-(4-{2-[4-(cyclopentanecarbonyl-amino)-phenoxy]-ethoxy}-phenyl)-2-methoxy-propionic    acid (Compound 368);-   (2S)-3-[4-(2-{4-[(furan-2-carbonyl)-amino]-phenoxy}-ethoxy)-phenyl]-2-methoxy-propionic    acid (Compound 369);-   (2S)-2-methoxy-3-[4-(2-{4-[(pyridine-3-carbonyl)-amino]-phenoxy}-ethoxy)-phenyl]-propionic    acid (Compound 370);-   (2S)-2-methoxy-3-{4-[2-(2-pyrrolidin-1-yl-phenoxy)-ethoxy]-phenyl}-propionic    acid (Compound 371);-   (2S)-2-methoxy-3-{4-[2-(pyridin-2-yloxy)-ethoxy]-phenyl}-propionic    acid (Compound 372);-   (2S)-2-methoxy-3-{4-[2-(2-morpholin-4-yl-phenoxy)-ethoxy]-phenyl}-propionic    acid (Compound 373);-   (2S)-3-{4-[2-(4′-tert-butyl-biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic    acid (Compound 374);-   (2S)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic    acid (Compound 375);-   (2R)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic    acid (Compound 376);-   (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-propoxy-propionic    acid (Compound 377);-   3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-ethoxy-propionic acid    (isomer 1) (Compound 378);-   3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-ethoxy-propionic acid    (isomer 2) (Compound 379).

The present invention also includes compounds represented by StructuralFormula (I), wherein Ar is the corresponding aromatic group from any oneof Compounds 1–379. Preferably, R₁ is para to the carbon atom bonded toW, W₁ or W₂ and is represented by Structural Formula (II), morepreferably Structural Formula (III) or (IV) and even more preferablyStructural Formula (V).

Also included are compounds represented by Structural Formulas (I) or(VI), wherein Phenyl Ring A is the corresponding phenyl or substitutedphenyl group from any one of Compounds 1–379 or from one of thecompounds disclosed in Examples 1–379. Preferably, R₁ is para to thecarbon atom bonded to W, W₁ or W₂ and is represented by StructuralFormula (II), more preferably Structural Formula (III) or (IV) and evenmore preferably Structural Formula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —(CH₂)₃—O— and Ar is the corresponding aromatic group fromany one of Compounds 1–379 or from one of the compounds disclosed inExamples 1–379. Preferably, R₁ is para to the carbon atom bonded to W,W₁ or W₂ and is represented by Structural Formula (II), more preferablyStructural Formula (III) or (IV) and even more preferably StructuralFormula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —(CH₂)₄—O— and Ar is the corresponding aromatic group fromany one of Compounds 1–379 or from one of the compounds disclosed inExamples 1–379. Preferably, R₁ is para to the carbon atom bonded to W,W₁ or W₂ and is represented by Structural Formula (II), more preferablyStructural Formula (III) or (IV) and even more preferably StructuralFormula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —(CH₂)₅—O— and Ar is the corresponding aromatic group fromany one of Compounds 1–379 or from one of the compounds disclosed inExamples 1–379. Preferably, R₁ is para to the carbon atom bonded to W,W₁ or W₂ and is represented by Structural Formula (II), more preferablyStructural Formula (III) or (IV) and even more preferably StructuralFormula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —CH₂—C≡CH— and Ar is the corresponding aromatic group fromany one of Compounds 1–379 or from one of the compounds disclosed inExamples 1–379. Preferably, R₁ is para to the carbon atom bonded to W,W₁ or W₂ and is represented by Structural Formula (II), more preferablyStructural Formula (III) or (IV) and even more preferably StructuralFormula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —(CH₂)₂—C≡CH— and Ar is the corresponding aromatic groupfrom any one of Compounds 1–379 or from one of the compounds disclosedin Examples 1–379. Preferably, R₁ is para to the carbon atom bonded toW, W₁ or W₂ and is represented by Structural Formula (II), morepreferably Structural Formula (III) or (IV) and even more preferablyStructural Formula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —(CH₂)₃—C≡CH— and Ar is the corresponding aromatic groupfrom any one of Compounds 1–379 or from one of the compounds disclosedin Examples 1–379. Preferably, R₁ is para to the carbon atom bonded toW, W₁ or W₂ and is represented by Structural Formula (II), morepreferably Structural Formula (III) or (IV) and even more preferablyStructural Formula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —(CH₂)₄—C≡CH— and Ar is the corresponding aromatic groupfrom any one of Compounds 1–379 or from one of the compounds disclosedin Examples 1–379. Preferably, R₁ is para to the carbon atom bonded toW, W₁ or W₂ and is represented by Structural Formula (II), morepreferably Structural Formula (III) or (IV) and even more preferablyStructural Formula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —(CH₂)₅—C≡CH— and Ar is the corresponding aromatic groupfrom any one of Compounds 1–379 or from one of the compounds disclosedin Examples 1–379. Preferably, R₁ is para to the carbon atom bonded toW, W₁ or W₂ and is represented by Structural Formula (II), morepreferably Structural Formula (III) or (IV) and even more preferablyStructural Formula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —CH₂CO— and Ar is the corresponding aromatic group from anyone of Compounds 1–379 or from one of the compounds disclosed inExamples 1–379. Preferably, R₁ is para to the carbon atom bonded to W,W₁ or W₂ and is represented by Structural Formula (II), more preferablyStructural Formula (III) or (IV) and even more preferably StructuralFormula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —(CH₂)₂CO— and Ar is the corresponding aromatic group fromany one of Compounds 1–379 or from one of the compounds disclosed inExamples 1–379. Preferably, R₁ is para to the carbon atom bonded to W,W₁ or W₂ and is represented by Structural Formula (II), more preferablyStructural Formula (III) or (IV) and even more preferably StructuralFormula (V).

Also included are compounds represented by Structural Formula (I),wherein W is —(CH₂)₃CO— and Ar is the corresponding aromatic group fromany one of Compounds 1–379 or from one of the compounds disclosed inExamples 1–379. Preferably, R₁ is para to the carbon atom bonded to W,W₁ or W₂ and is represented by Structural Formula (II), more preferablyStructural Formula (III) or (IV) and even more preferably StructuralFormula (V).

Also included are compounds represented by Structural Formula (I),wherein W is represented by the following structural formula:

and Ar is the corresponding aromatic group from any one of Compounds1–379 or from one of the compounds disclosed in Examples 1–379.Preferably, R₁ is para to the carbon atom bonded to W, W₁ or W₂ and isrepresented by Structural Formula (II), more preferably StructuralFormula (III) or (IV) and even more preferably Structural Formula (V).

Also included are compounds represented by Structural Formula (I),wherein W is represented by the following structural formula:

and Ar is the corresponding aromatic group from any one of Compounds1–379 or from one of the compounds disclosed in Examples 1–379.Preferably, R₁ is para to the carbon atom bonded to W, W₁ or W₂ and isrepresented by Structural Formula (II), more preferably StructuralFormula (III) or (IV) and even more preferably Structural Formula (V).

Also included are compounds represented by Structural Formula (I),wherein Ar—O—W— is the corresponding group from any one of Compounds1–379 or from one of the compounds disclosed in Examples 1–379.Preferably, R₁ is para to the carbon atom bonded to W and is representedby Structural Formula (II), more preferably Structural Formula (III) or(IV) and even more preferably Structural Formula (V).

Also included are compounds represented by Structural Formula (I),wherein Ar is the corresponding aromatic group from any one of Compounds1–379 or from one of the compounds disclosed in Examples 1–379, W is—CH(CH₃)W₃CH(CH₃)O— and W₃ is a covalent bond, methylene or ethylene.Preferably, R₁ is para to the carbon atom bonded to W and is representedby Structural Formula (II), more preferably Structural Formula (III) or(IV) and even more preferably Structural Formula (V).

Also included are compounds represented by Structural Formula (I),wherein Ar is the corresponding aromatic group from any one of Compounds1–379 or from one of the compounds disclosed in Examples 1–379, W is—W₄C(═O)W₅O— or —W₄C(═CH₂)W₅O— and W₄ and W₅ are independently methyleneor ethylene. Preferably, R₁ is para to the carbon atom bonded to W andis represented by Structural Formula (II), more preferably StructuralFormula (III) or (IV) and even more preferably Structural Formula (V).

Prodrugs are compounds of the present invention, which have chemicallyor metabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention that arepharmaceutically active in vivo. Prodrugs include acid derivatives wellknown to practitioners of the art, such as, for example, esters preparedby reaction of the parent acidic compound with a suitable alcohol, oramides prepared by reaction of the parent acid compound with a suitableamine. Simple aliphatic or aromatic esters derived from acidic groupspendent on the compounds of this invention are preferred prodrugs. Insome cases it is desirable to prepare double ester type prodrugs such as(acycloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.Particularly preferred esters as prodrugs are methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, andN,N-diethylglycolamido.

Methyl ester prodrugs may be prepared by reaction of the acid form of acompound of the present invention in a medium such as methanol with anacid or base esterification catalyst (e.g., NaOH, H₂SO₄). Ethyl esterprodrugs are prepared in similar fashion using ethanol in place ofmethanol.

Morpholinylethyl ester prodrugs may be prepared by reaction of thesodium salt of a compound of the present invention (in a medium such asdimethylformamide) with 4-(2-chloroethyl)morpholine hydrochloride(available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No.C4,220-3).

The term “pharmaceutically acceptable” means that the carrier, diluent,excipients and salt must be compatible with the other ingredients of theformulation, and not deleterious to the recipient thereof.Pharmaceutical formulations of the present invention are prepared byprocedures known in the art using well-known and readily availableingredients.

Also included in the present invention are pharmaceutically acceptablesalts, hydrates, stereoisomers and solvates of the compounds of thepresent invention and mixtures of such compounds, salts, hydrates,stereoisomers and/or solvates.

By virtue of its acidic moiety, certain compounds of the presentinvention form salts with pharmaceutically acceptable bases. Such apharmaceutically acceptable salt may be made with a base which affords apharmaceutically acceptable cation, which includes alkali metal salts(especially sodium and potassium), alkaline earth metal salts(especially calcium and magnesium), aluminum salts and ammonium salts,as well as salts made from physiologically acceptable organic bases suchas trimethylamine, triethylamine, morpholine, pyridine, piperidine,picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine,2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,N-benzyl-β-phenethylamine, dehydroabietylamine,N,N′-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine,quinine, quinoline, and basic amino acid such as lysine and arginine.These salts may be prepared by methods known to those skilled in theart.

Compounds of the present invention that are substituted with a basicgroup, may exist as salts with pharmaceutically acceptable acids. Thepresent invention includes such salts. Examples of such salts includehydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures,succinates, benzoates and salts with amino acids such as glutamic acid.

Certain compounds of the present invention may contain one or morechiral centers, and exist in different optically active forms. Whencompounds of the present invention contain one chiral center, thecompounds exist in two enantiomeric forms and the present inventionincludes both enatiomers and mixtures of enantiomers, such as racemicmixtures. The enantiomers may be resolved by methods known to thoseskilled in the art, for example by formation of diastereoisomeric saltswhich may be separated, for example, by crystallization; formation ofdiastereoisomeric derivatives or complexes which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography,selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic esterification; or gas-liquid or liquidchromatography in a chiral environment, for example on a chiral supportfor example silica with a bound chiral ligand or in the presence of achiral solvent. It will be appreciated that where the desired enantiomeris converted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a compound of the present invention has one or more chiralsubstituent it may exist in diastereoisomeric forms. Thediastereoisomeric pairs may be separated by methods known to thoseskilled in the ark for example chromatography or crystallization and theindividual enantiomers within each pair may be separated as describedabove. The present invention includes each diastereoisomer of suchcompounds and mixtures thereof.

Certain compounds of the present invention may exist in zwitterionicform and the present invention includes each zwitterionic form andmixtures thereof.

Certain compounds of the present invention and their salts may exist inmore than one crystal form. Polymorphs of compounds of the presentinvention form part of this invention and may be prepared bycrystallization of a given compound under different conditions. Forexample, using different solvents or different solvent mixtures forrecrystallization; crystallization at different temperatures; variousmodes of cooling, ranging from very fast to very slow cooling duringcrystallization. Polymorphs may also be obtained by heating or melting acompound of the present invention followed by gradual or fast cooling.The presence of polymorphs may be determined by solid probe nmrspectroscopy, ir spectroscopy, differential scanning calorimetry, powderX-ray diffraction or such other techniques.

A “subject” is a mammal, preferably a human, but can also be an animalin need of veterinary treatment, e.g., companion animals (e.g., dogs,cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, andthe like) and laboratory animals (e.g., rats, mice, guinea pigs, and thelike).

“Treatment” or “treating”, as it is used herein, refers to boththerapeutic treatment and prophylactic treatment. “Therapeutictreatment” refers to preventing the further progression or amelioratethe symptoms associated with a disease or condition. “Prophylactictreatment” refers to inhibiting, preventing or delaying the onset of thesymptoms of a disease or condition in a subject who is at risk for thedisease or condition. “Prophylactic treatment” also includes reducingthe severity of the symptoms of a disease or condition by treating asubject at risk for developing the disease or condition before symptomsappear.

The language an “effective amount” or “pharmaceutically effectiveamount” is intended to include an amount that is sufficient to mediate adisease or condition and prevent its further progression or amelioratethe symptoms associated with the disease or condition. An “effectiveamount” or “pharmaceutically effective amount” can also include anamount sufficient to prevent or delay the onset of a disease orcondition in a patient at risk for developing the disease or condition,i.e., prophylactic treatment. Such amount when administeredprophylactically to a patient can also be effective to lessen theseverity of the mediated condition. Such an amount is intended toinclude an amount that is sufficient to modulate a PPAR receptor, suchas a PPARγ or PPARα receptor, which mediate a disease or condition.Conditions mediated by PPARα or PPARγ receptors include diabetesmellitus, cardiovascular disease, Syndrome X, obesity andgastrointestinal disease. Other such diseases are described below.

The compounds of the present invention and the pharmaceuticallyacceptable salts, solvates, stereoisomers and hydrates thereof havevaluable pharmacological properties and can be used in pharmaceuticalpreparations containing the compound or pharmaceutically acceptablesalts, esters or prodrugs thereof, in combination with apharmaceutically acceptable carrier or diluent. They are useful astherapeutic substances in r treating (therapeutically orprophylactically) hyperglycemia, dyslipidemia, Type II diabetes, Type Idiabetes, hypertriglyceridemia, syndrome X, insulin resistance, heartfailure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia,hypertension, obesity, anorexia bulimia, polycystic ovarian syndrome,anorexia nervosa cardiovascular disease (especially atherosclerosis) orother diseases where insulin resistance is a component or otherdisorders mediated by a PPAR receptor. Suitable pharmaceuticallyacceptable carriers include inert solid fillers or diluents and sterileaqueous or organic solutions. The active compound will be present insuch pharmaceutical compositions in amounts sufficient to provide thedesired dosage amount in the range described herein. Techniques forformulation and administration of the compounds of the instant inventioncan be found in Remington: the Science and Practice of Pharmacy, 19^(th)edition, Mack Publishing Co., Easton, Pa. (1995).

For oral administration, the compound or salts thereof can be combinedwith a suitable solid or liquid carrier or diluent to form capsules,tablets, pills, powders, syrups, solutions, suspensions and the like.

The tablets, pins, capsules, and the like may also contain a binder suchas gum tragacanth, acacias, corn starch or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid, a lubricant such as magnesium stearate; and asweetening agent such as sucrose lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor. Such compositions and preparations should contain atleast 0.1 percent of active compound. The percentage of active compoundin these compositions may, of course, be varied and may conveniently bebetween about 2 percent to about 60 percent of the weight of the unit.The amount of active compound in such therapeutically usefulcompositions is such that an effective dosage will be obtained.

The active compounds can also be administered intranasally as, forexample, liquid drops or spray. For oral or nasal inhalation, thecompounds for use according to the present invention are convenientlydelivered in the form of a dry powder inhaler; or an aerosol spraypresentation from pressurized packs or a nebuliser, with the use of asuitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of gelatin for use in an inhaler or insufflatormay be formulated containing a powder mix of the compound and a suitablepowder base such as lactose or starch.

For parental administration the compounds of the present invention, orsalts thereof can be combined with sterile aqueous or organic media toform injectable solutions or suspensions. For example, solutions insesame or peanut oil, aqueous propylene glycol and the like can be used,as well as aqueous solutions of water-soluble pharmaceuticallyacceptable salts of the compounds. Dispersions can also be prepared inglycerol, liquid polyethylene glycols and mixtures thereof in oils.Under ordinary conditions of storage and use, these preparations containa preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that each syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against anycontamination. The carrier can be solvent or dispersion mediumcontaining, for example, water, ethanol, polyol (e.g. glycerol,propylene glycol and liquid polyethylene glycol), propylene glycol andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils. The injectable solutions prepared in this manner can then beadministered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition, to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation, for example, subcutaneously orintramuscularly or by intramuscular injection. Thus, for example, as anemulsion in an acceptable oil, or ion exchange resins, or as sparinglysoluble derivatives, for example, as sparingly soluble salts.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.

When used herein Syndrome X includes pre-diabetic insulin resistancesyndrome and the resulting complications thereof, insulin resistance,non-insulin dependent diabetes, dyslipidemia, hyperglycemia obesity,coagulopathy, hypertension and other complications associated withdiabetes. The methods and treatments mentioned herein include the aboveand encompass the therapeutic treatment and/or prophylaxis of any one ofor any combination of the following: hyperglycemia, dyslipidemia, TypeII diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulinresistance, heart failure, diabetic dyslipidemia, hyperlipidemia,hypercholesteremia, hypertension, obesity, anorexia bulimia, polycysticovarian syndrome, anorexia nervosa, cardiovascular disease (especiallyatherosclerosis) or other diseases where insulin resistance is acomponent or other diosorders mediated by a PPAR receptor.

The compositions are formulated and administered in the same generalmanner as detailed herein. The compounds of the instant invention may beused effectively alone or in combination with one or more additionalactive agents depending on the desired target therapy. Combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of the present invention and oneor more additional active agents, as well as administration of acompound of the present invention and each active agent in its ownseparate pharmaceutical dosage formulation. For example, a compound ofan insulin secretogogue such as biguanides, thiazolidinediones,sulfonylureas, insulin, or α-glucosidose inhibitors can be administeredto the patient together in a single oral dosage composition such as atablet or capsule, or each agent administered in separate oral dosageformulations. Where separate dosage formulations are used, a compound ofthe present invention and one or more additional active agents can beadministered at essentially the same time, i.e., concurrently, or atseparately staggered times, i.e., sequentially. Combination therapy isunderstood to include all these regimens.

An example of combination therapeutic or prophylactic treatment ofatherosclerosis may be wherein a compound of the present invention or asalt thereof is administered in combination with one or more of thefollowing active agents: antihyperlipidemic agents; plasma HDL-raisingagents; antihypercholesterolemic agents, fibrates, vitamins, aspirin,and the like. As noted above, the compounds of the present invention canbe administered in combination with more than one additional activeagent.

Another example of combination therapy can be seen in treating(therapeutically or prophylactically) diabetes and related disorderswherein the compounds of the present invention and salts thereof can beeffectively used in combination with, for example, sulfonylureas,biguanides, thiazolidinediones, α-glucosidase inhibitors, other insulinsecretogogues, insulin as well as the active agents discussed above fortreating atherosclerosis.

Other examples of therapeutic agents which can be used in combinationwith the compounds of the present invention include insulin sensitizers,PPARγ agonists, glitazones, troglitizone, pioglitazone, englitazone,MCC-555, BRL 49653, biguanides, metformin, phenformin, insulin, insulinminetics, sulfonylureas, tolbutamide, glipizide, alpha-glucosidaseinhibitors, acarbose, cholesterol lowering agent, HMG-CoA reductaseinhibitors, lovastatin, simvastatin, pravastatin, fluvastatin,atrovastatin, rivastatin, other statins, sequestrants, cholestyramine,colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran,nicotinyl alcohol, nicotinic acid, a nicotinic acid salt, PPARαagonists, fenofibric acid derivatives, gemfibrozil, clofibrate,fenofibrate, benzafibrate, inhibitors of cholesterol absorption,beta-sitosterol, acyl CoA:cholesterol acyltransferase inhibitors,melinamide, probucol, PPARδ agonists, antiobesity compounds,fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat,neuropeptide Y5 inhibitors, β₃ adrenergic receptor agonists, and ilealbile acid transporter inhibitors.

An effective amount of a compound of the present invention can be usedfor the preparation of a medicament useful for treating (therapeutic andprophylactic) hyperglycemia, dyslipidemia, Type II diabetes, Type Idiabetes, hypertriglyceridemia, syndrome X, insulin resistance, heartfailure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia,hypertension, obesity, anorexia bulimia, polycystic ovarian syndrome,anorexia nervosa, cardiovascular disease (especially atherosclerosis),lowering tryglyceride levels, raising the plasma level of high densitylipoprotein or other diseases where insulin resistance is a component orother disorders mediated by a PPAR receptor. Included is treating,preventing or reducing the risk of developing atherosclerosis, and forpreventing or reducing the risk of having a first or subsequentatherosclerotic disease event in mammals, particularly in humans. Ingeneral an effective amount of a compound of the present invention (1)reduces serum glucose levels of a patient, or more specifically HbA1c,typically by about 0.7%; (2) reduces the serum triglyceride levels of apatient, typically by about 20%; and/or (3) increases the serum HDLlevels in a patient, preferably about 30%.

Additionally, an effective amount of a compound of the present inventionand an effective amount of one or more of the active agents listed abovecan be used together for the preparation of a medicament useful for theabove-described treatments.

Preferably compounds of the invention or pharmaceutical formulationscontaining these compounds are in unit dosage form for administration toa mammal. The unit dosage form can be any unit dosage form known in theart including, for example, a capsule, an IV bag, a tablet, or a vial.The quantity of active ingredient (viz., a compound of the presentinvention or salts thereof) in a unit dose of composition is atherapeutically effective amount and may be varied according to theparticular treatment involved. It may be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration that may be by a variety of routes including oral,aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal and intranasal.

Pharmaceutical formulations of the invention are prepared by combining(e.g., mixing) an effective amount of a compound of the inventiontogether with a pharmaceutically acceptable carrier or diluent. Thepresent pharmaceutical formulations are prepared by known proceduresusing well-known and readily available ingredients.

In making the compositions of the present invention, the activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier that may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, lyophilized solid or paste, semi-solid, orliquid material which acts as a vehicle, or can be in the form oftablets, pills, powders, lozenges, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium), orointment, containing, for example, up to 10% by weight of the activecompound. The compounds of the present invention are preferablyformulated prior to administration.

For the pharmaceutical formulations any suitable carrier known in theart can be used. In such a formulation, the carrier may be a solid,liquid, or mixture of a solid and a liquid. For example, for intravenousinjection the compounds of the invention may be dissolved in at aconcentration of about 0.05 to about 5.0 mg/ml in a 4% dextrose/0.5% Nacitrate aqueous solution.

Solid form formulations include powders, tablets and capsules. A solidcarrier can be one or more substance that may also act as flavoringagents, lubricants, solubilisers, suspending agents, binders, tabletdisintegrating agents and encapsulating material.

Tablets for oral administration may contain suitable excipients such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate,together with disintegrating agents, such as maize, starch, or alginicacid, and/or binding agents, for example, gelatin or ac acia, andlubricating agents such as magnesium stearate, stearic acid, or talc.

In powders the carrier is a finely divided solid that is in admixturewith the finely divided active ingredient. In tablets the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

Advantageously, compositions containing the compound of the presentinvention or the salts thereof may be provided in dosage unit form,preferably each dosage unit containing from about 1 to about 500 mg beadministered although it will, of course, readily be understood that theamount of the compound or compounds of the present invention actually tobe administered will be determined by a physician, in the light of allthe relevant circumstances.

Powders and tablets preferably contain from about 1 to about 99 weightpercent of the active ingredient that is the novel compound of thisinvention. Suitable solid carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methyl cellulose, sodium carboxymethyl cellulose, lowmelting waxes, and cocoa butter.

The following pharmaceutical formulations 1 through 8 are illustrativeonly and are not intended to limit the scope of the invention in anyway. “Active Ingredient”, refers to a compound according to the presentinvention or salts thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesiumstearate  10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active Ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed  10 Stearic acid  5 Total 665 mgThe components are blended and compressed to form tablets each weighing665 mg

Formulation 3

An aerosol solution is prepared containing the following components:

Weight Active Ingredient 0.25 Ethanol 25.75 Propellant 22(Chlorodifluoromethane) 74.00 Total 100.00The Active Ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

Tablets, each containing 60 mg of Active ingredient, are made asfollows:

Active Ingredient   60 mg Starch   45 mg Microcrystalline cellulose   35mg Polyvinylpyrrolidone (as 10% solution in water)   4 mg Sodiumcarboxymethyl starch  4.5 mg Magnesium stearate  0.5 mg Talc   1 mgTotal  150 mg

The Active Ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Formulation 5

Capsules, each containing 80 mg of Active Ingredient, are made asfollows:

Active Ingredient  80 mg Starch  59 mg Microcrystalline cellulose  59 mgMagnesium stearate  2 mg Total 200 mg

The Active Ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 6

Suppositories, each containing 225 mg of Active Ingredient, are made asfollows:

Active Ingredient   225 mg Saturated fatty acid glycerides 2,000 mgTotal 2,225 mgThe Active Ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of Active Ingredient per 5 ml dose,are made as follows:

Active Ingredient   50 mg Sodium carboxymethyl cellulose   50 mg Syrup1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purifiedwater to total   5 ml

The Active Ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 8

An intravenous formulation maybe prepared as follows:

Active Ingredient   100 mg Isotonic saline 1,000 ml

The solution of the above materials generally is administeredintravenously to a subject at a rate of 1 ml per minute.

The compounds of the present invention, in general, may be preparedaccording to the Reaction Schemes described below. When describingvarious aspects of the present compounds, the terms “Tail”, “Linker” and“Head” are used as their concept is illustrated below in GeneralReaction Scheme.

As shown in General Reaction Scheme, the compounds of the presentinvention can be divided into three regions designated as Tail, Linkerand Head. By a retrosynthetic analysis, key bond disconnections occurbetween each of these 3 regions. According to route A, a nucleophilictailpiece is coupled to an electrophilic compound linker-headpiece,which in turn is derived by coupling the linker region with theheadpiece by route B. Alternately according to route C, the headpiececan be coupled to the compound tailpiece-linker, derived by coupling thenucleophilic tailpiece with the electophilic linker by route D. Thefollowing reaction schemes illustrate more detailed synthetic routes toprepare the compounds of the present invention.

Reaction Scheme A shows the preparation of a general headpiece of thepresent compounds. Condensation of an aromatic aldehyde (1) with analpha-alkoxyacetic acid ester (2) in the presence of a suitable base,such as lithium bis(trimethylsilyl)amide yields hydroxyester (3). Thefree hydroxyl group is converted into a leaving group by treatment witheither methanesulfonyl chloride or trifluoroacetic anhydride. When thearomatic alcohol is protected as a benzyl ether (Pg is PhCH₂),exhaustive hydrogenolysis using hydrogen over Pd/C yields compound (5).Ester hydrolysis of (5) using aqueous hydroxide solution affords acidcompound (6), which can be resolved into the corresponding enantiomersby using an appropriate chiral amine, such as (−)-cinchonidine. The acid(7) can be esterified using the appropriate alcohol under acidicconditions, such as ethanol and sulfuric acid, or an alkyl halide underbasic conditions, such as cesium carbonate in DMF to give compound (8).

An alternate route to the headpiece is shown in Reaction Scheme B. Theketone function of ketoacid (9) is subjected to a reducing agent, suchas B-chloro-diisopinocamphenylborane, to give hydroxyacid (10). Thephenolic hydroxyl group is then protected with the protecting group togive compound (11). The compound (11) reacted with a dimethyl ketalfollowed by phenol ether cleavage gives an dioxolanone intermediate,which affords a 2-alkoxyacid upon treatment with a suitable Lewis acid,such as TiCl₄ and a reducing reagent, such as a trialkylsilane.Esterification yields 2-alkoxyester (12). Alternatively, acid (11) canbe esterified to yield ester (13), which can be treated with anelectrophile such as an alkyl halide, and an additive such as NaH orsilver (I) oxide to afford ether compound (14).

As shown in Reaction Scheme C, a Claisen rearrangement can be used toalkylate the headpiece. Aryl alcohol (15) is treated with an alkylbromide in the presence of a suitable base, such as NaH to give allylether (16). Heating the ether compound (16) in dimethylaniline affordsthe allylated headpiece compound (17).

As shown in Reaction Scheme D, halogen substitution can be introducedinto the headpiece by treating aryl alcohol (18) with anN-halosuccinimide in organic solvent to yield the compound (19). Thecompound (19) then undergoes a coupling reaction in the presence ofpalladium catalyst to yield the corresponding aryl and styrenylcompounds (20).

Reaction Scheme E illustrates a synthesis of the present compounds bythe general linker-headpiece route (General Scheme, routes A and B). Theheadpiece compoud (21) is coupled with a suitably monoprotected diolusing a trialkylphosphine or triarylphosphine and an azodicarboxylatederivative (Mitsunobu conditions) to yield aryl ether (22). Deprotectionof the alcohol function in the linker affords the compound (23), whichthen undergoes Mitsunobu coupling reaction with a tailpiece aryl alcohol(ArOH) to give compound (24). Further ester hydrolysis affords acidcompound (25). Alternatively, the alcohol compound (23) can be convertedto the corresponding halide (26) using a carbon tetrahalide andtriphenylphosphine. Treatment of compound (26) with a tailpiece arylalcohol (ArOH) in the presence of a suitable base, such as cesiumcarbonate affords compound (24), which then undergoes hydrolysis to giveacid compound (25).

As shown in Reaction Scheme F, the compounds of the present inventioncan be prepared by the general tailpiece-linker to headpiece route(General Scheme, route C). The headpiece compound of alcohol (27) istreated with a tailpiece-inker halide (ArO-L-X) in the presence of asuitable base, such as potassium or cesium carbonate to afford thecompound (28), which then undergoes ester hydrolysis to yield acidcompound (29).

As shown in Reaction Scheme G, the headpiece can be attached to a resinallowing for a solid phase synthesis of the target compounds. Carboxylicacid (30) is attached to a suitable resin, such as the Wang resin, usingan appropriate coupling reagent, such as diisopropyl carbodiimide(DIPC). Cleavage of the aryl alcohol protecting group, such as atert-butyldimethylsilyl ether (t-BuMe₂Si) with the appropriate reagent,such as tetra-n-butylammonium fluoride gives aryl alcohol (32). The tailand linker regions are introduced as described in Reaction Schemes E andF to produce the compound (33). The carboxylic acid (34) can be releasedfrom the resin under suitable conditions, such as trifluoroacetic acid.

Reaction Scheme H illustrates a synthetic route to prepare the compoundsof the present invention having alkynyl linkers. The headpiece compound(35) can be converted to the corresponding aryl triflate (36) (or aryliodide) using phenyl triflamide and an appropriate base, such as NaH.The palladium catalyzed coupling reaction of compound (36) with analkynyl alcohol gives the linker-headpiece intermediate (37). Couplingof compound (37) with various tailpiece alcohols can be achieved asdescribed in Reaction Scheme E to afford the compound (38), which thenundergoes a hydrolysis to yield the acid compound (40).

Alternative to Reaction Scheme H, the headpiece compound of triflate(41) can be combined with a tailpiece-linker to give the coupledcompound (42) in one step as shown in Reaction Scheme I. The compound(42) then undergoes a hydrolysis to give the acid compound (43).

As shown in Reaction Scheme 3, the headpiece compound of triflate (44)can be coupled with trimethylsilylacetylene using palladium catalysis togive the acetylenic headpiece (45) after fluoride mediated cleavage ofthe silyl group. The alkyne (45) is hydrolyzed under aqueous acidicconditions to the methyl ketone, which is then brominated with asuitable agent, such as copper (I) bromide to give bromoketone (46).Treatment of the compound (46) with a tailpiece aryl alcohol in thepresence of a suitable base, such as potassium carbonate and aqueousbase hydrolysis affords the acid compound (47).

As shown in Reaction Scheme K, an alkyne function in the linker regionof the present compounds can be modified. The alkyne can be oxidized toketone to give compound (49) by using an appropriate oxidizing agent,such as mercuric oxide. The ketone can be further modified to thecorresponding oximes (51) by treatment with an alkoxyamine followed byhydrolysis. Alternatively, the alkynyl function can be reduced to thealkylene as in compound (50) by using an appropriate reducing agent,such as hydrogen over palladium-on-carbon.

Reaction Scheme L illustrates various synthetic routes to the linkerregion. In route (a), 1,3-propane diol (52) is converted to the cyclicsulfonate ester (53) upon treatment with thionyl chloride followed byappropriate oxidation reagents, such as ruthenium trichloride and sodiumperiodate. Ring opening of the intermediate (53) is effected upontreatment with a tailpiece alcohol and a suitable base such as potassiumtert-butoxide, followed by an acidic workup procedure to give the linkeralcohol compound (54). The alcohol is then converted to the halide byusing an appropriate reagent, such as a carbontetrahalide and atriarylphosphine to afford the compound (55). In route (b), the compoundof dibromo-linker (56) is reacted with approximately one mole equivalentof the tailpiece aryl alcohol in the presence of a suitable base, suchas potassium carbonate to give the bromo-ether compound (57).

In route (c), the compound of diol-linker (58) is coupled withapproximately one mole equivalent of the tailpiece alcohol underMitsunobu reaction conditions to give the hydroxy-ether compound (59).

In route (d), 1,3-propane diol (60) is converted to the halide (61),which is then reacted with the headpiece aryl alcohol under theMitsunobu reaction condition to give the bromo-ether compound (62).

Reaction Scheme M illustrates the synthetic routes to compounds witharyl-containing linkers. In route (a), The compound of headpiecetriflate (60) is coupled with an arylboronic acid in the presence ofpalladium catalyst. Reduction of the intermediate aldehyde using asuitable reagent such as sodium borohydride, affords the arylic alcoholcompound (61). The compound (61) can be coupled with the tailpiece arylalcohol (ArOH) under Mitsunobu conditions followed by ester hydrolysisto give the acid compound (62).

In route (b), the headpiece alcohol (63) is coupled with approximatelyone mole equivalent of aryl dibromide in the presence of palladiumcatalyst to give aryl bromide (64). The compound (64) is then coupledsimilarly to the tailpiece aryl alcohol (ArOH) followed by esterhydrolysis to afford the acid compound (65).

Reaction Scheme N shows a synthetic route to modify the tailpiece regionof the present compounds. The compound of para-fluorobenzophenone (66)is treated with a suitable nucleophile such as secondary amines andalkoxides, and then subjected to ester hydrolysis to give the acidcompound (67).

The carbonyl function of benzophenone (68) can be reduced by using anappropriate reagent, such as hydrogen over palladium-on-carbon to yieldthe corresponding alcohol (69) after ester hydrolysis. The ketone moietyof compound (68) can be also modified to the corresponding oximes (70)by treatment with an alkoxyamine followed by hydrolysis.

Reaction Scheme O shows the synthetic routes to prepare the tailpieceregion of the compounds. A Claisen rearrangement is used to alkylate thetailpiece aryl ring as shown in route (a). Aryl alcohol (71) is treatedwith an alkyl bromide in the presence of a suitable base, such as NaH togive alkyl ether (72). Heating this ether in dimethylaniline gives thealkylated headpiece (73).

Solid phase methods to synthesize the tailpiece are described in route(b). Aryl alcohol is coupled to a suitable resin, such as the Wang resinunder Mitsunobu conditions. Coupling the resin with a nitro aryl alcoholgives an intermediate that is reduced under-appropriate conditions, suchas tin (II) chloride in DMF to give aniline (74). The nitrogen functionis reacted further with suitable reagents, such as isocyanates, acidchlorides or chloroformates to give the corresponding ureas, carbamatesand amides, respectively. Cleavage from the resin under acidicconditions, such as trifluoroacetic acid in dichloromethane affords theamino substituted tailpiece of aryl alcohol compound (75).

Alternatively, coupling the resin with an iodo aryl alcohol gives iodideintermediate (76). The aryl iodide (76) then can be coupled directlywith aryl boronic acids under palladium catalysis to give biaryltailpiece aryl alcohols (77) upon cleavage from the resin under acidiccondition. Iodide intermediate (76) can also be converted to thetrialkylstannane (78) in the presence of palladium catalyst. Subsequentpalladium catalyzed coupling with suitable reagents, such as acidchloride and upon cleavage from the resin under acidic condition affordthe carbonyl substituted tailpiece aryl alcohol compound (79).

EXEMPLIFICATION

Instrumental Analysis

¹H NMR spectra were recorded on Varian 400 MHz, Bruker 200, 300 or 500MHz spectromethers at ambient temperature. Data are reported as follows:chemical shift in ppm from internal standard tetramethylsilane on the δscale, multiplicity (b=broad, s=singlet, d=doublet, t=triplet,q=quartet, qn=quintet and m=multiplet), integration, and couplingconstant (Hz). ¹³C NMR were recorded on a Bruker 200, 300 or 500 MHzspectromether at ambient temperature. Chemical shifts are reported inppm from tetramethylsilane on the δ scale, with the solvent resonanceemployed as the internal standard (CDCl₃ at 77.0 ppm and DMSO-d₆ at 39.5ppm). High resolution mass spectra were obtained on VG ZAB 3F or VG 70SE spectromethers. Analytical thin layer chromatography was performed onEM Reagent 0.25 mm silica gel 60-F plates. Visualization wasaccomplished with UV light

Standard Synthesis Procedures

Certain standard synthesis procedures were used in preparing many of theexemplified compounds of the present invention. These StandardProcedures were:

Standard Procedure for Mitsounobu coupling hydrolysis procedure (A): Asolution of triphenylphosphine (1.42 mmol) in 10 mL of dry THF wastreated at 0° C. with diethylazodicarboxylate (1.42 mmol) and stirredfor 20 min A solution of(2S)-3-[4-(3-Hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester (1.19 mmol) and 4-phenylphenol (1.42 mmol) in 5 mL of dry THF wasadded to the solution, and the mixture stirred at room temperatureovernight. The mixture was concentrated to dryness under vacuum andpurified by silica gel chromatography (silica gel, hexanes ethyl acetate10:1 to 3:1). Fractions with Rfs 0.5 and 0.42 (hexanes/ethyl acetate2:1) corresponding to the couple compound and starting phenol,respectively, were combined and concentrated to dryness. The mixture wasdissolved in 4 mL of 1N NaOH and 12 mL of methanol and stirred at roomtemperature until TLC indicated the disappearance of starting material.The methanol was removed under vacuum, and the aqueous solution wasdiluted with 20 mL of brine and washed with diethyl ether (3×15 mL). Theaqueous phase was acidified with 1N HCl (pH 1-2) and extracted withethyl acetate (3×15 mL). The organic layer dried (MgSO₄) andconcentrated under vacuum.

Standard Procedure for the Mitsounobu coupling procedure (B): A solutionof triphenylphosphine (1.42 mmol) in 10 mL toluene or THF was treated at0° C. with DEAD or DIAD (1.42 mmol) and stirred for 20 min. A solutionof (2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (1.19mmol) and the corresponding alcohol (1.42 mmol) in 5 mL of toluene orTHF was added to the solution, and the mixture stirred at roomtemperature overnight. The mixture was concentrated to drynessunder-vacuum and purified by silica gel chromatography

Standard hydrolysis Procedure (C):(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid ethyl ester (0.5 g, 1.17 mmol) was dissolved in 20 mL of 1N NaOH(or LiOH) and 60 mL of methanol and was stirred at room temperatureuntil TLC indicated the disappearance of starting material (ca. 3 h).The methanol was removed under vacuum, and the aqueous solution dilutedwith 20 mL of brine and washed with diethyl ether (3×60 mL). The aqueousphase was acidified with 1N HCl (until pH 1-2) and extracted with ethylacetate (3×60 mL). The organic layer dried (MgSO₄) and concentratedunder vacuum.

Standard Procedure for Monoprotection of diols (D): A solution of thecorresponding diol (1 eq) in dry THF was cooled to 0° C. Sodium hydride(1 eq) was added, and the mixture reaction was stirred 30 min at thattemperature. Tert-butyldimethylsilyl chloride (0.95 eq) was added, andthe mixture was stirred at room temperature overnight. Then a 10% Na₂CO₃solution was added and the mixture was extracted with ethyl acetate. Thecombined organic layers were washed with brine; dried (MgSO₄) andconcentrated in vacuo. The residue was purified by silica gelchromatography.

Standard Procedure for the cleveage of the protected alcohols (E): Amixture solution of the corresponding protected alcohol in THF wastreated with tetrabutylamonium fluoride (1M in THF) (2 eq). The solutionwas stirred at room temperature until reaction is completed by TLC, thenquenched with water and extracted with Ethyl Acetate to give a crudeproduct which was purified by silica gel chromatography.

Standard Procedure (F): The reaction was carried out in a polypropylenesyringe equipped with a polypropylene frit. A suspension of theresin-linked phenol (1 eq) was suspended in THF (0.02 M). A solution of1,3-propanediol (5 eq) in THF was added followed by a mixture oftriphenylphosphine (5 eq) and diisopropylazo-dicarboxylate (5 eq) inTHF. The mixture was shaken at room temperature overnight. The reactionsolvent was removed, and the resin was washed sequentially with THF(2×), CH₂Cl₂ (2×), DMF (2×), CH₂Cl₂ (2×), methanol and CH₂Cl₂ (3×). Theresultant polymer was dried under vacuum overnight to produce thetargeted immobilized alcohol.

Standard Procedure (G): The reaction was carried out in a polypropylenesyringe equipped with a polypropylene frit. A suspension of theresin-linked alcohol (1 eq) was suspended in a mixture 1:1 THF/CH₂Cl₂(0.015 M. A solution of phenol (10 eq) dissolved in a mixture of 1:1THF/CH₂Cl₂ was added followed by a mixture of triphenylphosphine (5 eq)and diisopropylazo-dicarboxylate (5 eq) in THF/CH₂Cl₂ 1:1. The mixturewas shaken at room temperature overnight, and the reaction solvent wasremoved. The resin was washed sequentially with 1:1 THF/CH₂Cl₂ (2×), THF(2×), CH₂Cl₂ (2×), DMF (2×), CH₂Cl₂ (2×), methanol, and CH₂Cl₂ (2×). Theresin was dried under vacuum for 5 h and treated with 50% TFA in CH₂Cl₂.The solution was filtered and concentrated, and the residue was purifiedby HPLC-MS chromatography to produce the desired product.

Standard Procedure (H): Lithium hydroxide 1N solution in water (0.245mL) was added to a solution of the ester (0.073 mmol) in tetrahydrofuran(1 mL) at room temperature. The reaction mixture was stirred at roomtemperature for 1.5 hours, diluted with water (10 mL) and extracted withdiethyl ether (3×10 mL). The aqueous layer was acidified with 1N HCl topH 1 and extracted with Diethyl ether (5×15 mL). The combined organiclayers were dried (MgSO₄), filtered and concentrated under vacuum toproduce the corresponding acid.

Standard Procedure (I): A mixture of the corresponding phenol (1 eq) andthe bromoalkyl derivative (1 eq) with K₂CO₃ (3 eq) were refluxed inacetonitrile overnight. Cooled the mixture reaction and concentrated todryness to give a crude which was purified by chromatography in silicagel to give the product.

Standard Procedure (J). A mixture of the corresponding phenol (1.5 eq),and the bromoalkyl derivative (1 eq) in DMF were treated with Cs₂CO₃ (3eq). The mixture reaction was stirred at room temperature overnight andthen filtered. Removed the DMF under vacuo and added methanol to theresidue treating the mixture with NaOH 1M (10 eq) and stirred for 3 h.The solvent was evaporated and the salts were dissolved in water. Theaqueous phase was acidified to pH 2 and extracted with dichloromethane,filtered through a hydrophobic syringe and the organic layer purified byHPLC-MS.

Example 1(2S)-3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionicacid

Step A(2S)-2-Methoxy-3-(4-trifluoromethanesulfoxy-phenyl)-propionic acid ethylester

To a solution of (S)-2-methoxy-3-hydroxyphenyl-propionic acid ethylester (0.388 g, 1.73 mmol) in 40 mL of dry THF cooled to −20° C. wasadded sodium hydride (0.073 g, 1.82 mmol, 60% oil dispersion). Themixture was stirred at −20° C. for 30 min. Phenyl triflimide (0.68 g,1.90 mmol) was added in one portion, and the solution was stirred atroom temperature overnight and concentrated to dryness under vacuum. Theresidue was partitioned between water (20 mL) and diethyl ether (20 mL).The layers were separated, and the aqueous solution was extracted withdiethyl ether (2×20 ml). The combined organic layers were washed with10% Na₂CO₃ (6×20 mL) and brine (20 mL), dried (MgSO₄), and concentratedto a yellow oil (574 mg, 97%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.34–7.16(m, 4H), 4.18 (q, 2H, J=7.0), 3.93 (dd, 1H, J=7.3, 5.6), 3.36 (s, 3H),3.05 (s, 1H), 3.02 (d, 1H, J=2.4 Hz), 1.22 (t, 3H, J=7.25).

Step B

(2S)-3-[4-(3-Hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester

A solution of(2S)-2-methoxy-3-(4-trifluoromethane-sulfonyloxy-phenyl)-propionic acidethyl ester (0.861 g, 2.53 mmol), propargyl alcohol (0.88 mL, 15.18mmol), triethylamine (1.41 mL, 10.12 mmol) anddichlorobis(triphenylphosphine)palladium (II) in 10 mL of dry DMF washeated to 90° C. for 2 hours. The reaction mixture was cooled to roomtemperature, diluted with 50 mL of water, and extracted with diethylether (3×30 mL). The combined organic layers were washed with 0.5 N HCl(2×20 mL) and brine (20 mL), dried (MgSO₄), and concentrated. Theresidue purified by column chromatography (silica gel, hexanes/ethylacetate 2:1, R_(f)0.17) to give a yellow-brown oil (0.211 g, 32%).¹H-NMR (200.15 MHz, CDCl₃): δ 7.35 (d, 2H, J=8.1), 7.18 (d, 2H, J=8.1),4.48 (s, 2H), 4.17 (q, 2H, J=7.3), 3.93 (dd, 1H, J=7.3, 5.7), 3.34 (s,3H), 3.02 (s, 1H), 2.99 (d, 1H, J=2.2), 1.8 (s, 1H), 1.22 (t, 3H,J=7.3).

Step C

(2S)-3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester using the standard Mitsunobu coupling-hydrolysis procedure(Standard Procedure A) to produce a white solid. Mp 111–112° C. ¹H-NMR(200.15 MHz, CDCl₃): δ 7.58–7.52 (m, 4H), 7.45–7.30 (m, 5H), 7.19 (d,1H, J=8.3), 7.10 (dd, 3H, J=6.7, 1.9), 4.94 (s, 2H), 3.98 (dd, 1H,J=7.5, 4.3); 3.37 (s, 3H), 3.13 (dd, 1H, J=14.5, 4.6), 2.99 (dd, 1H,J=14.2, 7.8). MS (ES) for C₂₅H₂₂O₄ [M+NH₄]⁺: 404, [M+Na]⁺:409.

Example 2(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionicacid:

The title compound was prepared from(2S)-3-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester (from Example 1, Step B) via the standard Mitsunobucoupling-hydrolysis procedure (Standard Procedure A) to produce a whiteoily solid. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.84–7.71 (m, 4H), 7.55–7.33(m, 5H), 7.17 (d, 2H, J=8.0), 7.07 (d, 2 H, J=8.8), 4.96 (s, 2H), 3.96(dd, 1H, J=7.7, 4.4), 3.35 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.97(dd, 1H, J=14.3, 7.3).

Example 3(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-prop-1-ynyl]-phenyl}-propionicacid:

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester via (from Example 1, Step B) the standard Mitsunobucoupling-hydrolysis procedure (Standard Procedure A) to produce a whiteoily solid (41%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.38–7.15 (m, 5H),7.02–6.76 (m, 8H); 4.86 (s, 2H), 3.98 (dd, 1H, J=7.3, 4.4), 3.36 (s,3H), 3.12 (dd, 1H, J=14.3, 4.4), 2.98 (dd, 1H, J=14.3, 7.3). MS (ES) forC₂₅H₂₂O₅ [M+NH₄]⁺: 420.2, [M+Na]⁺:425.2.

Example 4(2S)-3-{4-[3-(4-Fluoro-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester (from Example 1, Step B) via the standard Mitsunobucoupling-hydrolysis procedure (Standard Procedure A) to produce a whitesolid of the title compound. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.34 (d,J=8.1 Hz, 2 H); 7.16 (d, J=8.0 Hz, 2 H); 6.98–6.86 (m, 4 H); 4.84 (s, 2H); 3.97 (dd, J=7.7, 4.4 Hz, 1 H); 3.36 (s, 3 H); 3.12 (dd, J=14.3, 4.4Hz, 1 H); 2.98 (dd, J=14.3, 7.3 Hz, 1 H). MS (ES) for C₁₉H₁₇FO₄[M+NH₄]⁺: 346, [M+Na]⁺: 351.

Example 5(2S)-2-Methoxy-3-{4-[3-(3-phenyl-benzofuran-6-yloxy)-prop-1-ynyl]-phenyl}-propionicacid

Step A(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester

The title compound was prepared from(2S)-3-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester (0.060 g, 0.23 mmol) (from Example 1, Step B) in dry DMF (5 ml)and treated with triethyl amine (0.69 mmol) and mesylchloride (0.46mmol). The mixture reaction was stirred overnight and the crude productwas extracted with H₂O/Ether. The organic layer was dried andconcentrated to give a product that was purified in silica usingHexane/Ethyl Acetate (5/1) to give the title compound as an oil (0.020g, 30% yield). MS (ES) for C₁₅H₁₇ClO₃ [M+H]⁺: 281.2

Step B

(2S)-2-Methoxy-3-{4-[3-(3-phenyl-benzofuran-6-yloxy)-prop-1-ynyl]-phenyl}-propionicacid

A solution of(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Step A (0.071 mmol, 1 eq) in 0.7 ml of DMF in a 16×100 mmtube treated with 3-phenyl-6-hydroxybenzofurane (0.078 mmol, 1.1 eq)Cesium Carbonate (0.213 mmol 3 eq) and NaI (0.071 mmol, 1 eq) andstirred at room temperature overnight. The reactants were filtered andwashed with DMF several times. The solvent was evaporated under vacuoand the residue reconstituted in a mixture of Ethanol (2 ml) and NaOH(1M) (1 ml) and stirred at room temperature until reaction is completedby HPLC-MS. Then HCl (1M) was added (until pH=3) and the solvent wereeliminated under vacuo. The residue was reconstituted in CH₂Cl₂/H₂O andfiltered through a hidrofobic syringer. The organic layer was separated,concentrated and purified by HPLC-MS to get the title compound. MS(ES)for C₂₇H₂₂O₅ [M+H]⁺: 427.2.

Example 6(2S)-3-{4-[3-(4-Butyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and 4-n-butylphenol in a manner analogousto that described for Example 5, Step B. MS(ES) for C₂₃H₂₆O₄ [M−H]⁻:365.2

Example 7(2S)-2-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-prop-1-ynyl}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5 Step A and 4-(4-trifluoromethylPhenoxy)-phenol in amanner analogous to that described for Example 5, Step B. MS(ES) forC₂₆H₂₁F₃O₅ [M−H]⁻: 469.2

Example 8(2S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy)-prop-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5 Step A and 2-hydroxy-9-fluorenone in a manneranalogous to that described for Example 5, Step B. MS(ES) for C₂₆H₂₀O₅[M−H]⁻: 411.2

Example 9(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-prop-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and 7-hydroxyflavone in a manner analogousto that described for Example 5, Step B. MS(ES) for C₂₈H₂₂O₆[M+H]⁺:455.2.

Example 10(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and 2-fluoro-4-hydroxybenzophenone in amanner analogous to that described for Example 5, Step B. MS(ES) forC₂₆H₂₁FO[M+H]⁺: 433.2.

Example 11(2S)-2-Methoxy-3-{4-[3-(3-phenylamino-phenoxy)-prop-1-ynyl]-phenyl}-propionicacid

The title compound was prepare from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and 3-hydroxydiphenylamine in a manneranalogous to that described for Example 5, Step B. MS(ES) for CH₂₃H₂₃NO[M+H]⁺: 402.2.

Example 12(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and 4-fluoro-4′-hydroxybenzophenone in amanner analogous to that described for Example 5, Step B. MS(ES) forC₂₆H₂₁FO[M+H]⁺: 433.2.

Example 13(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-prop-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and 6-hydroxyflavone in a manner analogousto that described for Example 5, Step B. MS(ES) for C₂₈H₂₂O₆[M+H]⁺:455.2.

Example 14(2S)-3-(4-{3-[3-(4-Fluor-phenyl)-benzofuran-6-yloxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and 6-hydroxy-3-(4-fluorophenyl)benzofuranein a manner analogous to that described for Example 5, Step B. MS(ES)for C₂₇H₂₁FO₅ [M−H]⁻: 443.2.

Example 15(2S)-2-Methoxy-3-(4-{3-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-prop-1-ynyl}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and 4-cumylphenol in a manner analogous tothat described for Example 5, Step B. MS(ES) for C₂₈H₂₈O₄[M+NH₄]⁺:446.2.

Example 16(2S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-prop-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and benzyl-4-hydroxyphenylketone in amanner analogous to that described for Example 5, Step B. MS(ES) forC₂₇H₂₄O₅ [M−H]⁻: 427.2.

Example 17(2S)-3-{4-[3-(4-Benzyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 5, Step A and 4-hydroxydiphenylmethane in a manneranalogous to that described for Example 5, Step B. MS(ES) forC₂₆H₂₄O₄[M−H]⁻: 399.

Example 18(2S)-3-[4-(3-{4-[(2-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-prop-1-ynyl)-phenyl]-2-methoxy-propionicacid

(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionicacid from Example 10, (0.01 mmol, 1 eq) was mixed with Hydroxylaminechlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixturereaction was stirred overnight. The ethanol was evaporated under vacuoand HCl 0.5% was added to the residue to pH=3. Extracted with ethylacetate and concentrated to give the title product as a mixture of twooximes. MS(ES) for C₂₆H₂₂FNO₅ [M+H]⁺: 448.2, [M−H]⁻: 446.2.

Example 19(2S)-3-(4-{3-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionicacid

(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionicacid (0.01 mmol, 1 eq) (Example 2) was mixed with Hydroxylaminechlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixturereaction was stirred overnight. The ethanol was evaporated under vacuoand HCl 0.5% was added to the residue to pH=3. Extracted with EthylAcetate and concentrated to give the title product as a mixture of twooximes. MS(ES) for C₂₆H₂₃NO₅ [M+H]⁺: 430.2, [M−H]⁻: 428.2.

Example 20(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-prop-1-ynyl)-phenyl]-2-methoxy-propionicacid

(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-prop-1-ynyl}-phenyl)-2-methoxy-propionicacid from Example 12 (0.01 mmol, 1 eq) was mixed with Hydroxylaminechlorydrate (4 eq), pyridine (10 eq) and Ethanol (2 ml) and the mixturereaction was stirred overnight. The ethanol was evaporated under vacuoand HCl 0.5% was added to the residue to pH=3. Extracted with EthylAcetate and concentrated to give the title product as a mixture of twooximes. MS(ES) for C₂₆H₂₂FNO₅ [M+H]⁺: 448.2, [M−H]⁻: 446.2.

Example 21(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-[4-(5-Hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester

This compound was prepared form 4-pentyn-1-ol following the proceduredescribed in Example 1, Step B. Yellow-brown oil. ¹H-NMR (200.15 MHz,CDCl₃): δ 7.33 (d, 2H, J=8.1), 7.16 (d, 2H, J=8.1), 4.17 (q, 2H, J=7.3),3.92 (dd, 1H, J=7.3, 5.7), 3.80 (t, 2H, J=6.5), 3.34 (s, 3H), 3.01 (s,1H), 2.98 (d, 1H, J=2.4), 2.68 (t, 2H, J=6.2), 1.86 (br, 1H), 1.23 (t,3H, J=7.3).

Step B

(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester and 4-phenylphenol via the standard Mitsunobu coupling-hydrolysisprocedure (Standard Procedure A) to produce a white oily solid. ¹H-NMR(200.15 MHz, CDCl₃): δ 7.56–7.28 (m, 9H), 7.15 (d, 2H, J=8.4), 6.98 (d,2H, J=8.8), 4.15 (t, 2H, J=6.2), 3.97 (dd, 1H, J=7.7, 4.4), 3.36 (s,3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.97 (dd, 1H, J=14.3, 7.7), 2.62 (t,2H, J=7.0), 2.08 (qn, 2H, J=6.6).

Example 22(2S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid(Example 21, Step A) and 4-phenoxyphenol via the standard Mitsunobucoupling-hydrolysis procedure (Standard Procedure A) to produce a whiteoily solid. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.26–7.19 (m, 4H), 7.07 (d,2H, J=8.3), 6.98–6.78 (m, 7H), 4.01 (t, 2H, J=5.9), 3.91 (dd, 1H, J=7.3,4.3), 3.30 (s, 3H), 3.05 (dd, 1H, J=14.2, 4.3), 2.90 (dd, 1H, J=14.2,7.5), 2.54 (t, 2H, J=6.7), 1.98 (qn, 2H, J=6.4). MS (ES) forC₂₇H₂₆O₅[M+NH₄]⁺: 448, [M+Na]⁺: 453.

Example 23(2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid(Example 21, Step A) and 4-hydroxybenzophenone via the standardMitsunobu coupling-hydrolysis procedure (Standard Procedure A) toproduce a white oily solid. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.82–7.70 (m,3H), 7.54–7.43 (m, 4H), 7.31–7.23 (m, 2H), 7.14 (d, 2H, J=8.1), 6.95 (d,2H, J=8.8), 4.19 (d, 2H, J=5.9), 3.96 (dd, 1H, J=7.7, 4.4), 3.34 (s,3H), 3.09 (dd, 1H, J=14.3, 4.4), 2.95 (dd, 1H, J=14.3, 7.7), 2.61 (t,2H, J=7.0), 2.08 (qn, 2H, J=0.6).

Example 24(2S)-3-{4-[5-(4-Benzyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid

Step A3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester

To a solution of(2S)-3-[4-(5-Hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester from Example 21, Step A (0.17 mmol, 1 eq) in dichloromethane (5ml) and CBr₄ (0.34 mmol, 2 eq) at 0° C., Ph₃P was added (0.34 mmol, 2eq) partionwise and the mixture reaction was stirred 1 hour the solventwas removed under vacuo and the residue purified by flash chromatographyusing Hexane/Ethyl acetate as eluent (6:1) to give the title product in85% yield.

Step B

(2S)-3-{4-[5-(4-Benzyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid

A solution of 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionicacid ethyl ester from Step A (0.1 mmol, 1 eq) in 0.7 ml of DMF in a16×100 mm tube treated with 4-hydroxydiphenylmethane (0.11 mmol, 1.1 eq)and Cesium Carbonate (0.3 mmol, 3 eq) and stirred at room temperatureovernight. The reactants were filtered and washed with DMF severaltimes. The solvent was evaporated under vacuo and the residuereconstituted in a mixture of Ethanol (2 ml) and NaOH (1M) (1 ml) andstirred at room temperature until reaction is completed by HPLC-MS. ThenHCl (1M) was added (until pH=3) and the solvent were eliminated undervacuo. The residue was reconstituted in CH₂Cl₂/H₂O and filtered througha hidrofobic syringer. The organic layer was separated, concentrated andpurified by HPLC-MS to get the title compound. MS(ES) forC₂₈H₂₈O₄[M+NH₄]⁺: 446.2.

Example 25(2S)-3-(4-{5-[4-(4-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and 4-fluoro-4-hydroxybenzophenone in a manneranalogous to that described for Example 24, Step B. MS(ES) forC₂₈H₂₅F₃O₅[M+H]⁺: 461.2.

Example 26(2S)-2-Methoxy-3-(4-{5-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-pent-1-ynyl}-phenyl)-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester

From Example 24, Step A and 4-(4-trifluoromethylphenoxy)phenol in amanner analogous to that described for Example 24, Step B. MS(ES) forC₂₈H₂₅F₃O₅[M+NH₄]⁺: 516.2.

Example 27(2S)-2-Methoxy-3-{4-[5-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-pent-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and 7-hydroxyflavone in a manner analogous tothat described for Example 24, Step B. MS(ES) for C₃₀H₂₆O₆[M+H]⁺:483.2.

Example 28(2S)-2-Methoxy-3-{4-[5-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-pent-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and 6-hydroxyflavone in a manner analogous tothat described for Example 24, Step B. MS(ES) for C₃₀H₂₆O₆[M+H]⁺:483.2

Example 29(2S)-2-Methoxy-3-(4-{5-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-pent-1-ynyl}-phenyl)-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and 4-cumylphenol in a manner analogous to thatdescribed for Example 24, Step B. MS(ES) for C₃₀H₃₂O₄ [M+NH₄]⁺: 474.3

Example 30(2S)-2-Methoxy-3-{4-[5-(9-oxo-9H-fluoren-2-yloxy-pent-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and 2-hydroxy-9-fluorenone in a manner analogousto that described for Example 24, Step B. MS(ES) forC₈H₂₄O₅[M+H]⁺:441.2.

Example 31(2S)-2-Methoxy-3-{4-[5-(3-phenylamino-phenoxy)-pent-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24 Step A and 3-hydroxydiphenylamine in a manner analogousto that described for Example 24, Step B. MS(ES) forC₂₇H₂₇NO₄[M+H]⁺:430.2.

Example 32(2S)-3-(4-{5-[4-(2-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and 2-fluoro-4′-hydroxybenzophenone in a manneranalogous to that described for Example 24, Step B. MS(ES) forC₂₈H₂₅FO₅[M+H]⁺:461.2.

Example 33(2S)-2-Methoxy-3-{4-[5-(3-phenyl-benzofuran-6-yloxy)-pent-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and 6-hydroxy-4-phenylbenzophenone in a manneranalogous to that described for Example 24, Step B. MS(ES) forC₂₉H₂₆O₅[M+H]⁺:455.2.

Example 34(2S)-3-(4-{5-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and 3-(4′-fluorophenyl)-6-hydroxybenzophenone ina manner analogous to that described for Example 24, Step B. MS(ES) forC₂₉H₂₅PO₅[M+H]⁺:473.2.

Example 35(2S)-2-Methoxy-3-{4-[5-(4-phenylacetyl-phenoxy)-pent-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and benzyl-4-hydroxyphenylketone in a manneranalogous to that described for Example 24, Step B. MS(ES) forC₂₉H₂₅O₅[M−H]⁻:455.2.

Example 36(2S)-3-{4-[5-Butyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 24, Step A and 4-N-butylphenol in a manner analogous tothat described for Example 24, Step B. MS(ES) for C₂₅H₃₀O₄[M−H]⁻:393.2.

Example 37(2S)-3-[4-(5-{4-[(2-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pent-1-ynyl)-phenyl]-2-methoxy-propionic

(2S)-3-(4-{5-[4-(2-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionicacid from Example 32, (1 eq) was mixed with Hydroxylamine chlorydrate (4eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction wasstirred overnight. The ethanol was evaporated under vacuo and HCl 6.5%was added to the residue to pH=3. Extracted with Ethyl Acetate andconcentrated to give the title product as a mixture of two oximes.MS(ES) for C₂₈H₂₆FNO₅ [M+H]⁺: 476.2, [M−H]⁻: 474.2.

Example 38(2S)-3-[4-(5-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-pent-1-ynyl)-phenyl]-2-methoxy-propionicacid

(2S)-3-(4-{5-[4-(4-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionicacid from Example 25 (1 eq) was mixed with Hydroxylamine chlorydrate (4eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction wasstirred overnight. The ethanol was evaporated under vacuo and HCl 0.5%was added to the residue to pH=3. Extracted with Ethyl Acetate andconcentrated to give the title product as a mixture of two oximes.MS(ES) for C₂₈H₂₆FNO₅ [M+H]⁺: 476.2, [M−H]⁻: 474.2.

Example 39(2S)-3-(4-{5-[4-Hydroxyimino-phenyl-methyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionicacid

(2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid from Example 23, (1 eq) was mixed with Hydroxylamine chlorydrate (4eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction wasstirred overnight. The ethanol was evaporated under vacuo and HCl 0.5%was added to the residue to pH=3. Extracted with Ethyl Acetate andconcentrated to give the title product as a mixture of two oximes:MS(ES) for C₂₈H₂₇NO₅ [M+H]⁺: 458.2.

Example 40(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid

Step AToluene-4-sulfonic acid but-3-ynyl ester

A solution of 3-butyn-1-ol (1 mL, 13.31 mmol), p-toluenesulphenylchloride (2.519 g, 13.21 mmol), triethylamine (2.03 mL, 14.53 mmol) and4-dimethylaminopyridine (0.081 g, 0.66 mmol) in 20 mL of dichloromethanewere stirred at room temperature overnight. The solution was dilutedwith dichloromethane (20 mL), washed with 0.5N-HCl (40 mL) and brine (40mL), dried (MgSO₄), and concentrated to produce an oil (2.82 g, 95%).¹H-NMR (200.15 MHz, CDCl₃): δ 7.80 (d, 2H, J=8.3), 7.35 (d, 2H, J=8.1),4.10 (t, 2H, J=7.0), 2.55 (dt, 2H, J=2.7, 7.0), 2.45 (s, 3H), 1.97 (t,1H, J=2.7).

Step B

4-But-3-ynyloxy-biphenyl

A solution of 4-phenylphenol (0.774 g, 4.55 mmol) and potassiumtert-butoxide (0.51 g, 4.55 mmol) in toluene (20 mL) was stirred for 1 hat room temperature. Sodium iodide (0.068 g, 0.45 mmol) andtoluene-4-sulfonic acid but-3-ynyl ester (1.02 g, 4.55 mmol) were added,and the mixture heated to reflux for 24 hours. The mixture was cooled toroom temperature, diluted with diethyl ether (20 mL), washed with water(2×20 mL). The organic layer was dried (MgSO₄) and concentrated undervacuum. The residue was purified by silica gel chromatography (silicagel, hexanes/ethyl acetate 3:1, R_(f)0.57) to give an oil (140 mg, 14%).¹H-NMR (200.15 MHz, CDCl₃): δ 7.57–7.50 (m, 4H), 7.46–7.38 (m, 2H), 7.32(d, 1H, J=7.3), 7.02–6.95 (m, 2H), 4.15 (t, 2H, J=7.0), 2.71 (dt, 2H,J=2.7, 7.3), 2.06 (t, 1H, J=2.7).

Step C

(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid ethyl ester

To a solution of(2S)-2-methoxy-3-(4-trifluoro-methanesulfonyloxy-phenyl)-propionic acidethyl ester (1.157 g, 3.4 mmol) (Example 1, Step A) in 30 mL of degassedpiperidine was added 4-but-3-ynyloxy-biphenyl (0.9 g, 4.85 mmol),tetrakis(triphenylphosphine)palladium (0) (0.196 g, 0.17 mmol),triphenylphosphine (0.09 g, 0.34 mmol), and cooper (I) iodide (0.065 g,0.34 mmol). The solution was stirred for 3 h at 80° C. and cooled toroom temperature. The solvent was evaporated under vacuum, and theresidue was purified by column chromatography (silica gel,hexanes/diethyl ether 9:1, R_(f)0.27) to a brown oil (0.7 g, 48%).¹H-NMR (200.15 MHz, CDCl₃): δ 7.58–7.30 (m, 9H), 7.17 (d, 2H, J=8.0),7.02 (d, 2H, J=8.9), 4.22 (t, 2H, J=7.3), 4.18 (q, 2H, J=7.0), 3.93 (dd,1H, J=7.3, 5.6), 3.35 (s, 3H), 3.02 (s, 1H), 2.99 (d, 1H, J=2.4), 2.92(t, 2H, J=7.3), 1.24 (t, 3H, J=7.3).

Step D

(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[4-(biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid ethyl ester via the standard hydrolysis procedure C. The residuewas purified by chromatography (silica gel hexanes/ethyl acetate/aceticacid 50:50:1, R_(f)0.25) to produce a white solid (86%). ¹H-NMR (200.15MHz, CDCl₃): δ 7.57–7.51 (m, 4H), 7.45–7.30 (m, 5H), 7.19 (d, 2H,J=8.0), 7.01 (d, 2H, J=8.8), 4.20 (t, 2H, J=6.9), 3.98 (dd, 1H, J=7.7,4.4), 3.37 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 3.00 (dd, 1H, J=14.3,7.7), 2.91 (t, 2H, J=7.0).

Example 41(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-1-ynyl]-phenyl}-propionicacid

Step A1-But-3-ynyloxy-4-phenyloxybenzene

This compound was prepared from 4-phenoxyphenol and toluene-4-sulfonicacid but-3-ynyl ester (Example 40, Step A) following the proceduredescribed in Example 40, Step B. ¹H-NMR (200.15 MHz, CDCl₃): δ77.35–7.26 (m, 2H), 7.05–6.87 (m, 5H), 4.09 (t, 2H, J=7.0), 2.69 (dt,2H, J=2.4, 7.0), 2.05 (t, 1H, J=2.1).

Step B

(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-4-ynyl]-phenyl}-propionicacid

The title compound was prepared from 1-but-3-ynyloxy-4-phenyloxybenzeneand (2S)-2-methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionicacid ethyl ester (Example 1, Step A) following the procedure describedin Example 40, Step C. The ethyl ester derivative was contaminated withstarting triflate. The mixture was hydrolyzed using the StandardProcedure C. The residue was purified by chromatography (silica gel,hexanes/ethyl acetate-Acetic acid 50:50:1, R_(f)0.25) to produce a whitesolid (7%): ¹H-NMR (200.15 MHz, CDCl₃): δ 7.35–7.28 (m, 4H), 7.16 (d,2H, J=8.0), 7.02–6.87 (1H, 7H), 4.13 (t, 2H, J=7.0), 3.97 (dd, 1H,J=7.7, 4.4), 3.36 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.97 (dd, 1H,J=14.3, 7.7), 2.87 (t, 2H, J=7.0). MS (ES) fro C₂₆H₂₄O₅ [M+NH₄]⁺: 434.2,[M+Na]⁺: 439.2.

Example 42(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid

Step A(4-But-3-ynyloxy-phenyl)-phenyl-methanone

This compound was prepared from 4-hydroxybenzophenone andtoluene-4-sulfonic acid but-3-ynyl ester (Example 40, Step A) followingthe procedure described in Example 40, Step B (8%). ¹H-NMR (200.15 MHz,CDCl₃): δ 7.84–7.73 (m, 4 H), 7.57–7.43 (m, 3H), 6.97 (d, 2H, J=8.6),4.18 (t, 2H, J=7.0), 2.73 (dt, 2H, J=2.7, 7.0), 2.06 (t, 1H, J=2.7).

Step B

(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid ethyl ester

This compound was prepared from (4-but-3-ynyloxy-phenyl)-phenylmethanoneand (2S)-2-Methoxy-3-(4-trifluoromethane-sulfonyloxy-phenyl)-propionicacid ethyl ester (Example 1, Step A) following the procedure describedin Example 38, Step C (66%). ¹H-NMR (200.15 MHz, CDCl₃): δ 37.85–7.73(m, 4H), 7.57–7.43 (m; 3H), 7.34 (d, 2H, J=8.1), 7.16 (d, 2H, J=8.3),7.00 (d, 2H, J=8.6), 4.25 (t, 2H, J=7.0), 4.18 (q, 2H, J=7.0), 3.92 (dd,1H, J=7.3, 5.6), 3.34 (s, 3H), 3.01 (s, 1H), 2.98 (d, 1H, J=3.5), 2.93(t, 2H, J=7.0), 1.23 (t, 3H, J=7.3).

Step C

(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[4-(4-benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid ethyl ester via the standard hydrolysis procedure C to produce awhite solid. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.83–7.71 (m, 4H), 7.55–7.44(m, 3H), 7.32 (d, 2H, J=8.0), 7.16 (d, 2H, J=8.4), 6.97 (d, 2H, J=9.1),4.22 (t, 2H, J=7.0), 3.96 (dd, 1H, J=7.7, 4.4), 3.35 (s, 3H), 3.10 (dd,1H, J=13.9, 4.4), 2.98 (dd, 1H, J=13.9, 7.7), 2.91 (t, 2H, J=7.0).

Example 43(2S)-3-(4-{4-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-but-1-ynyl}-phenyl)-2-methoxy-propionicacid

(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid from Example 42, (1 eq) was mixed with Hydroxylamine chlorydrate (4eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction wasstirred overnight. The ethanol was evaporated under vacuo and HCl 0.5%was added to the residue to pH=3. Extracted with Ethyl Acetate andconcentrated to give the title product as a mixture of two oximes. MS(ES) for C₂₇H₂₅NO₅ [M+H]⁺: 444.2.

Example 44(2S)-3-(4-{4-[4-(4-Fluoro-benzoyl)-phenoxy]-but-1-ynyl}-phenyl)-2-methoxy-propionicacid

Step A(4-But-3-ynyloxy-phenyl)-(4-fluoro-phenyl)-methanone

This compound was prepared from 4-fluoro-hydroxybenzophenone andtoluene-4-sulfonic acid but-3-ynyl ester (Example 40, Step A) followingthe procedure described in Example 40, Step B.

Step B

(2S)-3-(4-{4-[4-(4-Fluoro-benzyl)-phenoxy]-but-1-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(4-But-3-ynyloxy-phenyl)-(4-fluoro-phenyl)-methanone and (2S)-2-methoxy3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid ethyl ester(Example 1, Step A) following the procedure described in Example 40,Step C. The ethyl ester derivative was contaminated with startingtriflate. The mixture was hydrolyzed using the standard hydrolysisprocedure C. The residue was purified by chromatography. MS(ES) forC₂₇H₂₃FO [M+H]⁺: 447.2.

Example 45(2S)-3-(4-{4-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-but-1-ynyl}-phenyl)-2-methoxy-propionicacid

Step A6-But-3-ylnyloxy-3-(4-fluoro-phenyl)-benzofuran

This compound was prepared from 6-hydroxy-3-(4-fluorophenyl)benzofuraneand toluene-4-sulfonic acid but-3-ynyl ester (Example 40, Step A)following the procedure described in Example 40, Step B.

Step B

(2S)-3-(4-{4-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-but-1-ynyl}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from6-But-3-ynyloxy-3-(4-fluoro-phenyl)-benzofuran and(2S)-2-methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acidethyl ester Example 1, Step A) following the procedure described inExample 40, Step C. The ethyl ester derivative was contaminated withstarting triflate. The mixture was hydrolyzed using the StandardProcedure C. The residue was purified by chromatography. MS(ES) forC₂₈H₂₃FO₅ [M−H]⁻: 457.2.

Example 46(2S)-2-Methoxy-3-(4-{4-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-but-1-ynyl}-phenyl)-propionicacid

Step A4-(3-butynyloxy)-4′-trifluoromethylphenyloxy phenyl

This compound was prepared from trifluoromethylphenoxyphenol andtoluene-4-sulfonic acid but-3-ynyl ester Example 40, Step A) followingthe procedure described in Example 40, Step B.

Step B

(2S)-2-Methoxy-3-(4-{4-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-but-1-ynyl}-phenyl)-propionicacid

The title compound was prepared from4-(3-butynyloxy)-4′-trifluoromethylphenyloxy phenyl and(2S)-2-methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acidethyl ester (Example 1, Step A) following the procedure described inExample 40, Step C. The ethyl ester derivative was contaminated withstarting triflate. The mixture was hydrolyzed using the StandardProcedure C. The residue was purified by chromatography. MS(ES) forC₂₇H₂₃F₃O₅ [M−H]⁻: 483.2.

Example 47(2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-7-yloxy-but-1-ynyl]-phenyl}-propionicacid

Step A3-[4-(4-Hydroxy-but-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester

This compound was prepared form 4-butyn-1-ol following the proceduredescribed in Example 1, Step B.

Step B

(2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-but-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from 7-hydroxyflavone by the Standardcoupling-hydrolisis Procedure A but using for the Mitsounobu reactiontoluene as solvent and DIAD instead DEAD. MS(ES) for C₂₉H₂₄O₆ [M+H]⁺:429.2.

Example 48(2S)-2-Methoxy-3-{4-[4-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-but-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from3-[4-(4-Hydroxy-but-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 47, Step A and 6-hydroxyflavone following the standardcoupling-hydrolysis procedure A using toluene as solvent and DIADinstead DEAD. MS(ES) for C₂₉H₂₄O₆ [M+H]⁺: 469.2.

Example 49(2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hex-1-ynyl]-phenyl}-propionicacid

Step A(2S)-3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester

To a solution of (2S)-(3-(4-iodophenyl)-2-methoxy-propionic acid ethylester (1.6 g, 4.81 mmol) in 100 mL of degassed piperidine was added5-hexin-1-ol (0.709 g, 724 mmol), tetrakis(triphenylphosphine)palladium(0) (0.278 g, 0.24 mmol), triphenylphosphine (0.125 g, 0.48 mmol), andcooper (I) iodide (0.091 g, 0.48 mmol). The solution was stirred for 3hours at 80° C. and cooled to room temperature. The solvent wasevaporated under vacuum, and the residue was purified by columnchromatography (silica gel, hexanes/ethyl acetate 3:1 to give titlecompound as a yellow oil (1.18 g, 74% yield). MS(ES) forC₁₈H₂₄O₄[M+NH₄]⁺: 322.2.

Step B

(2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hex-1-ynyl]-phenyl}-propionicacid

The title compound was prepared from3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl esterand 4-phenoxyphenol via the standard Mitsunobu coupling-hydrolysisprocedure (Standard Procedure A) to produce the title compound. MS(ES)for C₂₈H₂₈O₅[M+H]⁺: 445.2

Example 50(2S)-3-{4-[6-(4-Benzoyl-phenoxy)-hex-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 49, Step A) and 4-hydroxybenzophenone via the standardMitsunobu coupling-hydrolysis procedure (Standard Procedure A) toproduce the title compound. MS(ES) for C₂₉H₂₈O₅ [M+H]⁺: 457.2.

Example 51(2S)-3-{4-[6-(Biphenyl-4-yloxy)-hex-1-ynyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 49, Step A) and 4-phenylphenol via the standard Mitsunobucoupling-hydrolysis procedure (Standard Procedure A) to produce thetitle compound. MS(ES) for C₂₈H₂₈O₄[M+NH₄]⁺: 446.2.

Example 52(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propionicacid

A solution of triphenylphosphine (0.24 g, 0.915 mmol) in 5 mL of dry THFwas treated at 0° C. with diethylazodicarboxylate (0.159 g, 0.915 mmol)and stirred for 20 min. A solution of(2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester (Example 21, Step A) (0.18 g, 0.61 mmol) and 4-phenylphenol (0.156g, 0.915 mmol) in 2 mL of dry THF was added, and the mixture was stirredat room temperature overnight. The mixture was concentrated under vacuumand purified by silica gel chromatography (silica gel, hexanes/ethylacetate 10:1 to 3:1). Fractions with R_(f)s 0.48 and 0.45 (hexanes/ethylacetate 2:1) corresponding to the coupled compound and starting phenol,respectively, were combined and concentrated. The mixture was dissolvedin 5 mL of methanol and was treated with a mixture of 75 mg of mercury(II) oxide and 4% sulfuric acid in water. The solution was stirred at55° C. for 3 h, cooled to room temperature, diluted with saturatedaqueous NaHCO₃ (20 mL), and extracted with dichloromethane (4×20 mL).The combined organic layers were washed with brine (20 mL), dried(MgSO₄), and concentrated. The residue was dissolved in 6 mL of methanoland 2 mL of 1N NaOH and stirred for 2 hours. The methanol was evaporatedunder vacuum, and the aqueous solution was diluted with brine (6 mL) andwashed with diethyl ether (3×15 mL). The aqueous layer was acidifiedwith 1N HCl (pH 1–2) and extracted with ethyl acetate (3×15 mL). Thecombined extracts were dried (MgSO₄) and concentrated to a white solid(19%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.89 (d, 2H, J=8.4), 7.55–7.23 (m,9H), 6.93 (d, 2H, J=8.8), 4.06–3.99 (m, 3H), 3.38 (s, 3H), 3.18 (dd, 1H,J=4.3, 4.4), 3.03 (t+m, 3 H, J=6.9), 1.96–1.86 (m, 4H).

Example 53(2S)-3-{4-[5-(4-Benzoyl-phenoxy)-pentanoyl]-phenyl}-2-methoxy-propionicacid

A solution of triphenylphosphine (0.915 mmol) in 5 mL of dry THF wastreated at 0° C. with diethylazodicarboxylate (0.915 mmol) and stirredfor 20 min. A solution of(2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester (Example 21, Step A) (0.61 mmol) and 4-benzoylphenol (0.915 mmol)in 2 mL of dry THF was added, and the mixture was stirred at roomtemperature overnight. The mixture was concentrated under vacuum andpurified by silica gel chromatography (silica gel, hexanes/ethyl acetate10:1 to 3:1). Fractions with R_(f)s 0.48 and 0.45 (hexanes/ethyl acetate2:1) corresponding to the coupled compound and starting phenol,respectively, were combined and concentrated. The mixture was dissolvedin 5 mL of methanol and was treated with a mixture of 75 mg of mercury(II) oxide and 4% sulfuric acid in water. The solution was stirred at55° C. for 3 hours, cooled to room temperature, diluted with saturatedaqueous NaHCO₃ (20 mL), and extracted with dichloromethane (4×20 mL).The combined organic layers were washed with brine (20 mL), dried(MgSO₄), and concentrated. The residue was dissolved in 6 mL of methanoland 2 mL of 1N NaOH and stirred for 2 hours. The methanol was evaporatedunder vacuum, and the aqueous solution was diluted with brine (6 mL) andwashed with diethyl ether (3×15 mL). The aqueous layer was acidifiedwith 1N HCl (pH 1–2) and extracted with ethyl acetate (3×15 mL) thenconcentrated to give the title compound. ¹H-NMR (CDCl₃, 200.15 MHz):7.91–7.72 (m, 5H), 7.56–7.32 (m, 6H), 6.92 (d, 2H, J=8.9), 4.12–4.03 (m,3H), 3.42 (s, 3H), 3.19–3.05 (m, 4H), 1.95–1.92 (m, 4H).

Example 54(2S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pentanoyl]-phenyl}-propionicacid

A solution of triphenylphosphine (0.915 mmol) in 5 mL of dry THF wastreated at 0° C. with diethylazodicarboxylate (0.915 mmol) and stirredfor 20 min. A solution of(2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester (Example 21, Step A) (0.61 mmol) and 4-phenoxyphenol (0.915 mmol)in 2 mL of dry THF was added, and the mixture was stirred at roomtemperature overnight. The mixture was concentrated under vacuum andpurified by silica gel chromatography (silica gel, hexanes/ethyl acetate10:1 to 3:1). Fractions with R_(f)s 0.48 and 0.45 (hexanes/ethyl acetate2:1) corresponding to the coupled compound and starting phenol,respectively, were combined and concentrated. The mixture was dissolvedin 5 mL of methanol and was treated with a mire of 75 mg of mercury (II)oxide and 4% sulfuric acid in water. The solution was stirred at 55° C.for 3 hours, cooled to room temperature, diluted with saturated aqueousNaHCO₃ (20 mL), and extracted with dichloromethane (4×20 mL). Thecombined organic layers were washed with brine (20 mL), dried (MgSO₄),and concentrated. The residue was dissolved in 6 mL of methanol and 2 mLof 1N NaOH and stirred for 2 hours. The methanol was evaporated undervacuum, and the aqueous solution was diluted with brine (6 mL) andwashed with diethyl ether (3×15 mL). The aqueous layer was acidifiedwith 1N HCl (pH 1–2) and extracted with ethyl acetate (3×15 mL) thenconcentrated to give the title compound. ¹H-NMR (CDCl3, 200.15 MHz):7.91 (d, 2H, J=8.3), 7.36–7.27 (m, 4H), 7.07–6.83 (m, 7H), 4.08–3.96 (m,3H), 3.41 (s, 3H), 3.22 (dd, 1H, J=14.0, 4.3), 3.14–3.01 (m, 4H), 1.26(s, 1H).

Example 553-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionic acid

Step A(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionicacid ethyl ester

(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid ethyl ester (Example 42, Step B) (0.08 g, 0.17 mmol) was dissolvedin 4 mL of methanol. To this solution was added 3 mL of a solution of0.075 g, of mercury (II) oxide in 12 mL of 4% sulfuric acid. The mixturewas stirred at 55° C. for 3 hours, cooled to room temperature, anddiluted with 20 mL saturated NaHCO₃ solution.

The mixture was extracted with of dichloromethane (4×20 mL), and thecombined organic layers were dried (MgSO₄), and concentrated. Theresidue was purified by silica gel chromatography (silica gel,hexanes/ethyl acetate 3:1) to give a yellow oil (72%). ¹H-NMR (200.15MHz, CDCl₃): δ 7.92 (d, 2H, J=8.6), 7.83–7.72 (m, 4H), 7.60–7.42 (m,3H), 7.34 (d, 2H, J=8.6), 6.95 (d, 2H, J=8.9), 4.19 (q, 2H, J=7.3), 4.15(t, 2H, J=6.2), 3.97 (dd, 1H, J=7.3, 5.4), 3.35 (s, 3H), 3.19 (t, 2H,J=7.0), 3.08 (d, 1H, J=5.1), 3.07 (d, 1H, J=7.5), 2.27 (qn, 2H, J=6.2),1.24 (t, 3H, J=7.3).

Step B

3-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-{4-[4-(4-benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionicacid ethyl ester via the standard hydrolysis procedure C. White solid(71%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.90 (d, 2H, J=8.0), 7.80–7.70 (m,4H), 7.58–7.39 (m, 3H), 7.32 (d, 2H, J=8.4), 6.92 (d, 3H, J=9.1), 4.13(t, 2H, J=6.2), 4.02 (dd, 1H, J=7.3, 4.4), 3.38 (s, 3H), 3.20–3.00 (m,4H), 2.25 (qn, 2H, J=6.2).

Example 56(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butyryl]-phenyl}-propionicacid

Step A2S)-3-{4-[4-(4-phenoxy-phenoxy)-butyryl]-phenyl}-2-methoxy-propionicacid ethyl ester

(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-1-ynyl]-phenyl}-propionicacid ethyl ester (0.17 mmol) from Example 41, was dissolved in 4 ml ofmethanol. To this solution was added 3 ml of a solution of 0.075 g, ofmercury (II) oxide in 12 mL of 4% sulfuric acid. The mixture was stirredat 55° C. for 3 hour, cooled to room temperature, and diluted with 20 mLsaturated NaHCO₃ solution. The mixture was extracted with ofdichloromethane (4×20 mL), and the combined organic layers were dried(MgSO₄), and concentrated. The residue was purified by silica gelchromatography (silica gel, hexanes/ethyl acetate 3:1) to give a yellowoil.

Step B

(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butyryl]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-{4-[4-(4-phenoxy-phenoxy)-butyryl]phenyl}-2-methoxy-propionicacid ethyl ester via the standard hydrolysis procedure C. MS (ES) forC₂₆H₂₆O₆ [M+H]⁺: 435.2.

Example 57(2S)-3-[4-(Biphenyl-4-yloxy)-butyryl-phenyl]-2-methoxy-propionic acid

Step A(2S)-3-{4-[4-(4-phenylphenoxy)-butyryl]-phenyl}-2-methoxy-propionic acidethyl ester

(2S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid ethyl ester (0.17 mmol) from Example 40, Step C, was dissolved in 4ml of methanol. To this solution was added 3 ml of a solution of 0.075g, of mercury (II) oxide in 12 mL of 4% sulfuric acid. The mixture wasstirred at 55° C. for 3 hours, cooled to room temperature, and dilutedwith 20 mL saturated NaHCO₃ solution. The mixture was extracted with ofdichloromethane (4×20 mL), and the combined organic layers were dried(MgSO₄), and concentrated. The residue was purified by silica gelchromatography (silica gel, hexanes/ethyl acetate 3:1) to give a yellowoil.

Step B

(2S)-3-[4-(Biphenyl-4-yloxy)-butyryl-phenyl]-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-{4-[4-(4-phenylphenoxy)-butyryl]-phenyl}-2-methoxy-propionic acidethyl ester via the standard hydrolysis procedure C. MS (ES) forC₂₆H₂₆O₅ [M+H]⁺: 419.2.

Example 58(2S)-3-{4-[6-(Biphenyl-4-yloxy)-hexanoyl]-phenyl}-2-methoxy-propionicacid

A solution of triphenylphosphine (0.474 g, 1.8 mmol) in 50 mL of dry THFwas treated at 0° C. with diethylazodicarboxylate (1.8 mmol) and stirredfor 20 min. A solution of3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 49, Step A) (0.365 g, 1.2 mmol) and 4-phenylphenol (0.307 g,1.8 mmol) in 10 mL of dry THF was added, and the mixture was stirred atroom temperature overnight. The mixture was concentrated under vacuumand purified by silica gel chromatography (silica gel, hexanes/ethylacetate 10:1 to 3:1). Fractions with R_(f)s 0.48 and 0.45 (hexanes/ethylacetate 2:1) corresponding to the coupled compound and starting phenol,respectively, were combined and concentrated. The mixture was dissolvedin 5 mL of methanol and was treated with a mixture of 0–712 mg ofmercury (II) oxide and 12 ml of 4% sulfuric acid in water. The solutionwas stirred at 55° C. for 3 hours, cooled to room temperature, dilutedwith saturated aqueous NaHCO₃ (20 mL), and extracted withdichloromethane (4×20 mL). The combined organic layers were washed withbrine (20 mL), dried (MgSO₄), and concentrated. The residue wasdissolved in 6 mL of methanol and 2 mL of 1N NaOH and stirred for 2hours. The methanol was evaporated under vacuum, and the aqueoussolution was diluted with brine (6 mL) and washed with diethyl ether(3×15 mL). The aqueous layer was acidified with 1N HCl (pH 1–2) andextracted with ethyl acetate (3×15 mL). The combined extracts were dried(MgSO₄) and concentrated to give the title compound. MS(ES) forC₂₈H₃₀O₅[M+H]⁺: 447.2.

Example 59(2S)-2-Methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hexanoyl]-phenyl}-propionicacid

A solution of triphenylphosphine (1.8 mmol) in 50 mL of dry THF wastreated at 0° C. with diethylazodicarboxylate (1.8 mmol) and stirred for20 min. A solution of3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 49, Step A) (1.2 mmol) and 4-phenoxyphenol (1.8 mmol) in 10 mLof dry THF was added, and the mixture was stirred at room temperatureovernight. The mixture was concentrated under vacuum and purified bysilica gel chromatography (silica gel, hexanes/ethyl acetate 10:1 to3:1). Fractions with R_(f)s 0.48 and 0.45 (hexanes/ethyl acetate 2:1)corresponding to the coupled compound and starting phenol, respectively,were combined and concentrated. The mixture was dissolved in 5 mL ofmethanol and was treated with a mixture of 0.712 mg of mercury (II)oxide and 12 ml of 4% sulfuric acid in water. The solution was stirredat 55° C. for 3 hours, cooled to room temperature, diluted withsaturated aqueous NaHCO₃ (20 mL), and extracted with dichloromethane(4×20 mL). The combined organic layers were washed with brine (20 mL),dried (MgSO₄), and concentrated. The residue was dissolved in 6 mL ofmethanol and 2 mL of 1N NaOH and stirred for 2 hours. The methanol wasevaporated under vacuum, and the aqueous solution was diluted with brine(6 mL) and washed with diethyl ether (3×15 mL). The aqueous layer wasacidified with 1N HCl (pH 1–2) and extracted with ethyl acetate (3×15mL). The combined extracts were dried (MgSO₄) and concentrated to givethe title compound. MS(ES) for C₂₈H₃₀O₆[M+H]⁺: 463.2.

Example 60(2S)-3-{4-[6-(4-Benzoyl-phenoxy)-hexanoyl]-phenyl}-2-methoxy-propionicacid

A solution of triphenylphosphine (1.8 mmol) in 50 mL of dry THF wastreated at 0° C. with diethylazodicarboxylate (1.8 mmol) and stirred for20 min. A solution of3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 49, Step A) (1.2 mmol) and 4-phydroxybenzophenone (1.8 mmol) in10 mL of dry THF was added, and the mixture was stirred at roomtemperature overnight. The mixture was concentrated under vacuum andpurified by silica gel chromatography (silica gel, hexanes/ethyl acetate10:1 to 3:1). Fractions with R_(f)s 0.48 and 0.45 (hexanes/ethyl acetate2:1) corresponding to the coupled compound and starting phenol,respectively, were combined and concentrated. The mixture was dissolvedin 5 mL of methanol and was treated with a mixture of 0.712 mg ofmercury (II) oxide and 12 ml of 4% sulfuric acid in water. The solutionwas stirred at 55° C. for 3 hours, cooled to room temperature, dilutedwith saturated aqueous NaHCO₃ (20 mL), and extracted withdichloromethane (4×20 mL). The combined organic layers were washed withbrine (20 mL), dried (MgSO₄), and concentrated. The residue wasdissolved in 6 mL of methanol and 2 mL of 1N NaOH and stirred for 2hours. The methanol was evaporated under vacuum, and the aqueoussolution was diluted with brine (6 mL) and washed with diethyl ether(3×15 mL). The aqueous layer was acidified with 1N HCl (pH 1–2) andextracted with ethyl acetate (3×15 mL). The combined extracts were dried(MgSO₄) and concentrated to give the title compound. MS(ES) forC₂₉H₃₀O₆[M+H]⁺: 475.2.

Example 61(2S)-3-{4-[5-(Biphenyl-4-yloxy)-1-hydroxyimino-pentyl]-phenyl}-2-methoxy-propionicacid

(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propionicacid from Example 52, (1 eq) was mixed with Hydroxylamine chlorydrate (4eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction wasstirred overnight. The ethanol was evaporated under vacuo and HCl 0.5%was added to the residue to pH=3. Extracted with Ethyl Acetate andconcentrated to give the title product as a mixture of two oximes.MS(ES) for C₂₇H₂₉NO₅ [M+H]⁺: 448.2.2, [M−H]⁻: 446.2.

Example 62(2S,1′R*,2′S*)-3-(4-{2′-[4-(4-(Fluoro-benzoyl)-phenoxy]-cyclopentyloxy}-phenyl)-2-methoxy-propionicacid

Step Acis-2-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol

The title compound was prepared from meso-1,2-cyclopentanediol via theStandard Procedure D for the monoprotection of diols. The residue waspurified by silica gel chromatography (hexanes/ethyl 3:1, R_(f)0.55)(50%). ¹H-NMR (200.15 MHz, CDCl₃): δ 4.04 (dt, 1H, J=4.6, 6.2),3.95–3.89 (m, 1H), 2.59 (d, 1H, J=3.8), 1.88–1.49 (m, 6H), 0.91 (s, 9H),0.09 (s, 6H).

Step B

(2S,1′R,2′R)3-[4-(2′-Hydroxy-cyclopentyloxy)-phenyl]-2-methoxy-propionic acid ethylester

A solution of triphenylphosphine (0.634 g, 2.23 mmol) in 15 mL of dryTHF was treated, at 0° C. with diethylazodicarboxylate (0.368 mL, 0.2.45mmol) and stirred for 20 min. A solution of(2S)-2-methoxy-3-hydroxyphenylpropionic acid ethyl (0.5 g, 2.23 mmol)and cis-2-(tert-butyl-dimethyl-silanyloxy)cyclopentanol (0.531 g, 0.245mmol) min 5 mL of dry THF was added to the solution, and the mixture wasstirred at room temperature overnight. The mixture was concentratedunder vacuum and the residue was purified by silica gel chromatography(silica gel, hexanes/ethyl acetate 6:1). Fraction with R_(f)s 0.55(hexanes/ethyl acetate 3:1) corresponding to the coupled compound andstarting phenol, respectively, were collected and concentrated. Theresidue was dissolved in 4 mL of THF, and tetrabutylammonium fluoride(2.23 mL, 1 M in THF) was added. The solution was stirred for 2 hours atroom temperature, diluted with 30 mL of diethyl ether, and washed with1N HCl (2×20 mL). The organic solution was dried (MgSO₄) andconcentrated. The residue was purified by silica gel chromatography(silica gel, hexanes/ethyl acetate 3:1, R_(f) 0.9) to the product (60%).¹H-NMR (200.15 MHz, CDCl₃): δ 7.11 (d, 2H, J=8.6), 6.80 (d, 2H, J=8.9),4.43–4.40 (m, 1H), 4.23–4.12 (m, 4H); 3.90 (dd, 1H, J=7.0, 5.9); 3.35(s, 3H); 2.95 (d, 2H, J=6.7), 2.16–1.60 (m, 6H), 1.22 (t, 3H, J=7.0),0.88 (s, 9H), 0.05 (d, 3H, J=2.2).

Step C

(2S,1′R*,2′S*)3-(4-{2′-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclopentyloxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S,1′R,2′R)-3-[4-(2′-hydroxy-cyclopentyloxy)-phenyl]-2-methoxy-propionicacid ethyl ester and 4-fluoro-4-hydroxybenzophenone via the StandardProcedure A. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.82–7.67 (m, 4H), 7.18–7.06(m, 4H), 6.93 (d, 2H, J=8.9), 6.76 (d, 2H, J=8.6), 4.88–4.74 (m, 2H),3.97–3.94 (m, 1H), 3.39 (s, 3H); 3.09–2.89 (m, 2H); 2.23–1.98 (m, 6H).MS (ES) for C₂₈H₂₇FO₆ [M+H]⁺: 479.2, [M+Na]⁺: 501.2.

Example 63(2S)-(1′R,3′R)-2-Methoxy-3-{4-[1′,3′-dimethyl-3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid

Step A(2S,4S)-4-(tert-Butyl-dimethyl-silanyloxy)-pentan-2-ol

The title compound was prepared starting from (2S,4S)pentanediol usingthe Standard Procedure D. MS (ES) for C₁₁H₂₆O₂Si [M+H]₊: 219.2.

Step B

(2S)-(1′R,3′S)-3-{4-[3′-(tert-Butyl-dimethyl-silanloxy)-1′-methyl-butoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

The title compound was prepared using the Standard Procedure for theMitsounobu coupling B to give the product.

Step C

(2S)-(1′R,3′S)-3-[4-(3′-Hydroxy-1′-methyl-butoxy)-phenyl]-2-methoxy-propionicacid methyl ester

The title compound was prepared folowing the Standard Procedure E togive the product. MS (ES) for C₁₇H₂₆O₅ [M+H]⁺: 328.2.

Step D

(2S)-(1′R,2′R)-2-Methoxy-3-{4-[1′-methyl-3′-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propionicacid ethyl ester

The title compound was prepared following the Standard Mitsounobucoupling procedure B to give the corresponding product. MS (ES) forC₂₉H₃₄O₆ [M+NH₄]⁺: 496.2.

Step E

(2S)-(1′R,3′R)-2-Methoxy-3-{4-[1′,3′-dimethyl-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionicacid

The title compound was prepared by the Standard hydrolysis procedure Cof the compound from Step D to give the final compound as a gummy solid.¹H-NMR (CDCl₃, 200.15 MHz): 7.32–7.24 (m, 2H), 7.10–6.75 (m, 11H),4.70–4.50 (m, 2H), 3.95 (dd, 1H, J=7.3, 4.3), 3.36 (s, 3H), 3.06 (dd,1H, J=14.5, 4.6), 2.92 (dd, 1H, J=14.2, 7.5), 1.96 (dd, 2H, J=6.7, 5.4),1.31 (d, 6H, J=6.2).ppm. MS(ES) for C₂₇H₃₀O₆ [M+NH₄]⁺: 468.2, [M−H]⁻:449.2.

Example 64(2S)-(1′R,3′R)-3-{4-[3-(4-Benzoylphenoxy)-1′,3′-dimethylpropoxyl]-phenyl}2-methoxy-propionicacid

The title compound was prepared in a manner analogous that Example 63,starting from the (2S,4S)-pentanediol to give the final compound. ¹H-NMR(CDCl₃, 200.15 MHz): 9.24 (s, 1H), 7.75 (t, 1H, J=1.6), 7.70 (t, 1H,J=1.9), 7.69 (dd, 2H, J=12.6, 2.2), 7.59–7.40 (m, 3H), 7.04 (d, 2H,J=8.6), 6.85 (d, 2H, J=9.1), 6.69 (d, 2H, J=8.9), 4.87–4.72 (m, 1H),4.62–4.47 (m, 1H), 3.94 (dd, 1H, J=7.0, 5.6), 3.37 (s, 3H), 3.05–2.86(m, 2H), 1.99 (dd, 2H, J=6.7, 5.4), 1.36 (d, 3H, J=6.2), 1.30 (d, 3H,J=6.2).

Example 65(2S)-(1′S,3′S)-2-Methoxy-3-{4-[1′,3′-dimethyl-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionicacid

The title compound was prepared in a manner analogous that Example 63,starting from the (2R,4R)-pentanediol to give the final compound. ¹H-NMR(CDCl₃, 200.15 MHz): 7.33–7.25 (m, 2H), 7.12–6.76 (m, 11H), 4.71–4.49(m, 2H), 3.95 (dd, 1H, J=7.5, 4.6), 3.36 (s, 3H), 3.05 (dd, 1H, J=14.5,4.6), 2.93 (dd, 1H, J=14.2, 7.5), 1.96 (dd, 2H, J=7.0, 5.7), 1.31 (d,6H, J=6.2). MS(ES) for C₂₇H₃₀O₆ [M+NH₄]⁺: 468.2, [M−H]⁻: 449.2.

Example 66(2S)-(1′S,3′S)-3-{4-[3-(4-Benzoylphenoxy-1′,3′-dimethylpropoxyl]-phenyl}2-methoxy-propionicacid

The title compound was prepared in a manner analogous that Example 63,starting from the (2R,4R)-pentanediol to give the final compound ¹H-NMR(CDCl₃, 200.15 MHz): 7.76–7.41 (m, 7H), 7.02 (d, 2H, J=8.6), 6.83 (d,2H, J=8.9), 6.67 (d, 2H, J=8.6), 4.78 (dd, 1H, J=12.1, 6.2), 4.63–4.47(m, 1H), 3.99 (dd, 1H, J=6.2, 4.8), 3.41 (s, 3H), 3.08–2.87 (m, 2H),2.00 (dd, 2H, J=5.6, 12.4), 1.33 (dd, 6H, J=11.6, 6.2). MS(ES) forC₂₈H₃₀O₆ [M+H]⁺: 463.2, [M−H]⁻: 461.3.

Example 67(2S)-(1′R,2′R)-2-Methoxy-3-{4-[1′,2′-dimethyl-(4-phenoxy-phenoxy)-ethoxyl]-phenyl}-propionicacid

The title compound was prepared in a manner analogous that 63, startingfrom the (2S,3S)-butane-2,3-diol to give the final compound. ¹H-NMR(CDCl₃, 200.15 MHz): 7.94 (m, 1H), 7.34–7.26 (m, 3H), 7.17–6.83 (m,10H), 4.59–4.38 (m, 2H), 3.98 (dd, 1H, J=7.5, 4.6), 3.39 (s, 3H), 3.08(dd, 1H, J=14.2, 4.3), 2.95 (dd, 1H, J=14.2, 7.5), 1.36 (d, 6H, J=6.2).MS(ES) for C₂₆H₂₈O₆ [M+NH₄]⁺: 454.2, [M−H]⁻: 435.2.

Example 68(2S)-(1′R,2′R)-3-{4-[1-(4-Benzoylphenoxy)-1′,2′-dimethyl-ethoxyl]-phenyl}-2-methoxypropionicacid

The title compound was prepared in a manner analogous that Example 63,starting from the (2S,3S)butane-2,3-diol to give the final compound.¹H-NMR (CDCl₃, 200.15 MHz): 7.77 (t, 3H, J=8.9), 7.74 (s, 1H), 7.60–7.42(m, 3H), 7.14 (d, 2H, J=8.6), 6.96 (d, 2H, J=8.9), 6.84 (d, 2H, J=8.9),4.72–4.60 (m, 1H), 4.59–4.47 (m, 1H), 3.98 (dd, 1H, J=7.5, 4.6), 3.39(s, 3H), 3.08 (dd, 1H, J=14.5, 4.6), 2.95 (dd, 1H, J=14.2, 7.3), 1.42(d, 3H, J=6.2), 1.37 (d, 3H, J=6.2). MS(ES) for C₂₇H₂₈O₆ [M+H]⁺: 449.2,[M−H]⁻: 447.2.

Example 69(2S)-(1′S,4′S)-2-Methoxy-3-{4-[1′-methyl-4′-(4-phenoxy-phenoxy)-pentyloxy]-phenyl}-propionicacid

The title compound was prepared in a manner analogous that Example 63,starting from the (2R,5R)-hexane-2,5-diol to give the final compound.¹H-NMR (200.15 MHz, CDCl₃): 7.3–7.2 (m, 2H), 7.14 (d, 2H, J=8.6),7.1–6.8 (m, 9H), 4.4–4.3 (m, 2H), 3.97 (dd, 1H, J=7.6, 4.4), 3.39 (s,3H), 3.08 (dd, 1H, J=14.2, 4.4), 2.95 (dd, 1H, J=14.4, 7.6), 2.0–1.7 (m,4H), 1.31 (d, 6H, J=6.2) ppm.

Example 70(2S)-(1′S,4′S)-3-{4-[4-(4-Benzoyl-phenoxy)-1-methyl-pentyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared in a manner analogous that Example 63,starting from the (2R,5R)-hexane-2,5-diol to give the final compound.¹H-NMR (200.15 MHz, CDCl₃): 7.8–7.7 (m, 4H), 7.6–7.5 (m, 3H), 7.13 (d,2H, J=8.6), 6.90 (dd, 2H, J=7.0, 2.0), 6.79 (d, 2H, J=8.6), 4.51 (c, 1H,J=6.0), 4.35 (c, 1H, J=6.0), 3.98 (dd, 1H, J=7.2, 4.8), 3.39 (s, 3H),3.08 (dd, 1H, J=14.4, 4.8), 2.95 (dd, 1H, J=14.4, 7.2), 2.0–1.7 (m, 4H),1.35 (d, 3H, J=6.0), 1.30 (d, 3H, J=6.0) ppm.

Example 71(2S)-(1′R,4′R)-2-Methoxy-3-{4-[1′-methyl-4′-(4-phenoxy-phenoxy)-pentyloxy]-phenyl}-propionicacid

The title compound was prepared in a manner analogous that Example 63,starting from the (2S,5S)-hexane-2,5-diol to give the final compound.¹H-NMR (200.15 MHz, CDCl₃). 7.3–7.2 (m, 2H), 7.14 (d, 2H, J=8.4),7.1–6.7 (m, 9H), 4.4–4.2 (m, 2H), 3.96 (dd, 1H, J=7.4, 4.4), 3.37 (s,3H), 3.07 (dd, 1H, J=14.4, 4.4), 2.93 (dd, 1H, J=14.4, 7.4), 2.0–1.6 (m,4H), 1.30 (d, 6H, J=6.0) ppm.

Example 72(2S)-(1′R,4′R)-3-{4-[4-(4-Benzoyl-phenoxy)-1-methyl-pentyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared in a manner analogous that Example 63,starting from the (2S,5S)-hexane-2,5-diol to give the final compound.¹H-NMR (200.15 MHz, CDCl₃): 7.8–7.5 (m, 3H), 7.5–7.4 (m, 3H), 7.06 (d,2H, J=5.6), 6.82 (d, 2H, J=6.0), 6.71 (d, 2H, J=5.8), 4.44 (c, 1H,J=3.6), 4.28 (c, 1H, J=3.6), 3.88 (dd, 1H, J=9.6, 2.8), 3.29 (s, 3H),2.98 (dd, 1H, J=9.6, 2.8), 2.86 (dd, 1H, J=9.6, 5.0), 1.9–1.6 (m, 4H),1.27 (d, 3H, J=4.0), 1.21 (d, 3H, J=4.0) ppm.

Example 73(2S)-(1′S,2′S)-2-Methoxy-3-{4-[1′,2′-dimethyl-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionicacid

Step A(2R,3S)-3-(4-phenoxy-phenoxy)-butan-2-ol

A solution of (2R,3R)-butane-2,3-diol was monoprotected withtert-butyldimethylsilyl chloride using the Standard Procedure D, afterpurification by chromatography, the compound was coupling with4-phenoxyphenol using Standard Procedure B (in THF) and deprotected withtetrabutylamonium fluoride as Standard Procedure E to give the titlecompound as an oil. MS (ES) for C₁₆H₁₈O₃ [M+NH₄]⁺: 276.2.

Step B

(1R,2S)-Toluene-4-sulfonic acid 1-methyl-2-(4-phenoxy-phenoxy)-propylester

To a solution of compound from Step A (1 eq) in neat pyridine,p-Toluenesulfonic chloride (1.5 eq) was added and the mixture reactionwas stirred at room temperature over two days. The reaction was quenchedwith HCl 1N and extracted with ethyl acetate and washing the organiclayers with brine (3 times). The organic layers were dry andconcentrated in vacuo to give a residue which was purified by silica gelchromatography to give the title product. MS (ES) for C₂₃H₂₄O₅S[M+NH₄]⁺: 430.1.

Step C

(2S)-(1′S,2′S)-2-Methoxy-3-{4-[1′,2′-dimethyl-(4-phenoxy-phenoxy)-ethoxyl]-phenyl}-propionicacid ethyl ester

A solution of (1R,2S)-Toluene-4-sulfonic acid1-methyl-2-(4-phenoxy-phenoxy)-propyl ester from above Step (1 eq),potassium carbonate (3 eq) and2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (1 eq) inacetonitrile was refluxed overnight. The solution was evaporated todryness and chromatographied to get the title compound. MS (ES) forC₂₇H₃₀O₇ [M+NH₄]⁺: 482.4.

Step D

(2S)-(1′S,2′S)-2-Methoxy-3-{4-[1′,2′-dimethyl-(4-phenoxy-phenoxy)-ethoxyl]-phenyl}-propionicacid

The title compound was prepared using the Standard hydrolysis ProcedureC to give the final product as an oil. ¹H-NMR (CDCl₃, 200.15 MHz):7.34–7.26 (m, 3H), 7.16–6.83 (m, 10H), 4.58–4.41 (m, 2H), 3.98 (dd, 1H,J=7.3, 4.3), 3.39 (s, 3H), 3.14–2.89 (m, 2H), 1.35 (d, 6H, J=6.2).MS(ES) for C₂₆H₂₈O₆ [M+NH₄]₊: 454.3, [M−H]⁻: 435.1.

Example 74(2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionicacid

Step A2-(4-phenoxy-phenoxymethyl)-prop-2-en-1-ol

A solution of triphenylphosphine (1 eq) in toluene at 0° C. was treatedwith diethylazodicarboxylate (1 eq) and stirred for 20 min. Then asolution of 4-pehoxyphenol and 2-Methylene-propane-1,3-diol in toluenewas added to the solution and the mixture reaction was stirredovernight. Concentrated to dryness and chromatographied to give thetitle compound.

Step B

(2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionicacid ethyl ester

The title compound was prepared using Standard Mitsounobu couplingconditions B.

Step C

(2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared by using the Standard Procedure forhydrolysis C to give the final product as an oil. ¹H-NMR (CDCl₃, 200.15MHz): 8.09 (s, 1H), 7.34–6.86 (m, 13H), 5.41 (s, 2H), 4.62 (s, 4H), 3.98(dd, 1H, J=7.5, 4.6), 3.40 (s, 3H), 3.09 (dd, 1H, J=14.5, 4.6), 2.97(dd, 1H, J=14.5, 7.5).

Example 75(2S)-2-Methoxy-{4-[2-oxo-3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid

A solution of(2S)-2-Methoxy-{4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxyl]-phenyl}-propionicacid from Example 74, in dichloromethane at −78° C. was treated withozone until the solution turned blue. Washed with brine, dry andconcentrated to dryness to give the title compound. ¹H-NMR (CDCl₃,200.15 MHz): 7.35–6.83 (m, 13H), 4.86 (d, 4H, J=3.0), 3.98 (dd, 1H,J=7.3, 4.3), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.0), 2.97 (dd, 1H,J=14.5, 7.3). MS(ES) for C₂₅H₂₄O₇ [M+NH₄]⁺: 454.2, [M−H]⁻: 435.2.

Example 76(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxymethyl)-benzyloxy]-phenyl}-propionicacid

The title compound was prepared in a manner analogous that Example 74,starting from (3-Hydroxymethyl-phenyl)-ethanol to give the finalcompound. ¹H-NMR (200.15 MHz, CDCl₃): 7.50 (s, 1H), 7.40 (s, 2H), 7.28(d, 2H, J=8.6), 7.17 (d, 2H, J=8.6), 7.1–6.9 (m, 10H), 5.06 (s, 4H),3.99 (dd, 1H, J=7.2, 4.4), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.4, 4.6),2.97 (dd, 1H, J=14.2, 7.4) ppm.

Example 77(2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxymethyl)-benzyloxy]-phenyl}-propionicacid

The title compound was prepared in a manner analogous that Example 63,starting from (2-Hydroxymethyl-phenyl)-methanol to give the finalcompound. ¹H-NMR (200.15 MHz, CDCl₃): 7.5–7.4 (m, 2H), 7.4–7.3 (m, 2H),7.28 (d, 2H, J=8.0), 7.16 (d, 2H, J=8.6), 7.1–6.9 (m, 9H), 5.14 (s, 4H),3.95 (dd, 1H, J=7.4, 4.6), 3.37 (s, 3H), 3.07 (dd, 1H, J=14.2, 4.4),2.94 (dd, 1H, J=14.2, 7.6) ppm.

Example 78(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy-phenoxy]-phenyl}-propionicacid

Step A(2S)-3-[4-(3-Bromo-phenoxy)-phenyl]-2-methoxy-propionic acid ethyl ester

An ovendried resealable Schlenk tube was fitted with a rubber septum andwas cooled to room temperature under N₂ purge. The tube was charge withPd(OAc)₂(2.0 mol %), 2-(ditert-butylphosphino)biphenyl (0.03 eq),potassium phosphate (2 eq), 1,3-dibromobenzene (1 eq) and(2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (1,2 eq).The tube was capped with the septum and purged with N2, and then toluenewas added through the septum. The tube was sealed with a teflonscrewcap, and the reaction mixture was stirred at 100° C. for 16 hours.The solvent was removed and the residue was purified by chromatographyto afford the title compound.

Step B

(2S)-2-Methoxy-3-{4-[3-(phenoxy-phenoxy)-phenoxy]-phenyl}-propionic acidethyl ester

The title compound was porcepared using the same coupling proceduredescribed above for Step A with 4-phenoxyphenol and(2S)-3-[4-(3-Bromo-phenoxy)-phenyl]-2-methoxy-propionic acid ethylester.

Step C

(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-phenoxy]-phenyl}-propionicacid

The title compound was prepared from Step B by using Standar Procedurefor the hydrolysis C. MS (ES) for C₂₈H₂₄O₆ [M+Na]⁺: 479.

Example 79(2S)-3-[3′-(3-Benzoyl-phenoxymethyl)-biphenyl-4-yl]-2-methoxy-propionicacid

Step A(2S)-3-(3′-Hydroxymethyl-biphenyl-4-yl)-2-methoxy-propionic acid ethylester

A solution of (2S)2-Methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid ethylester (Example 1, Step A) (150 mg, 0.42 mmol), 3-formylphenyl boronicacid (126 mg, 0.842 mmol) and tetrakis(triphenylphosphine)-palladium (0)(15 mg, 0.013 mmol) in 11 ml of a mixture 20:1 toluene/ethanol togetherwith 2 ml of a 2N Na₂CO₃ was heated to 120° C. for 6 hours undernitrogen atmosphere. The reaction mixture was cooled to room temperatureand dilute with EtOAc (20 ml). It was washed with H₂O (3×5 ml) andsodium tartrate (3×5 ml). The combined organic layers were dried(MgSO₄), filtered and concentrated in vacuum. The resultant crude waspurified by column chromatography (silica gel, hexanes/ethyl acetate3:1). Fractions corresponding to the desired compound (R_(f): 0.27) werecollected and concentrate to dryness. The product was dissolved in MeOHcooled at 0° C., and sodium borohydride (3 eq) was added. The solutionwas stirred for 1 h. and then diluted with Ethyl-acetate (20 ml). It waswashed with H₂O (3×5 ml) and NaHCO₃ (3×5 ml). The combined organiclayers were dried (MgSO₄), filtered and concentrated in vacuum. Theresultant crude was purified by column (silica gel, hexanes/ethylacetate 2:1). Obtained a colorless oil (60 mg, 45%). ¹H-NMR (200.15 MHz,CDCl₃): δ 7.55–7.23 (m, 8H), 4.71 (s, 2H), 4.18 (q, 2H, J=7.0), 3.93(dd, 1H, J=7.3, 5.6), 3.35 (s, 3H), 3.05 (s, 1H), 3.02 (s, 1H), 1.25 (t,3H, J=7.25)

Step B

(2S)-3-[3′-(3-Benzoyl-phenoxymethyl)-biphenyl-4-yl]-2-methoxy-propionicacid

The title compound was prepared from (2S)3-(3′-Hydroxymethyl-biphenyl-4-yl)-2-methoxy-propionic acid ethyl ester(Step A) and 4-Hydroxybenzophenone via the standard Mitsunobucoupling-hydrolisis procedure (Standard Procedure A) to produce a whiteoily solid. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.83–7.33 (m, 15H), 7.03 (d,2H, J=8.1), 5.17 (s, 2H), 4.07 (dd, 1H, J=6.9, 3.7), 3.40 (s, 3H), 3.16(dd, 1H, J=14.1, 3.6), 3.06 (dd, 1H, J=14.1, 7.0).

Example 80(2S)-3-[4′-(4-Benzoyl-phenoxymethyl)-biphenyl-4-yl]-2-methoxy-propionicacid

Step A(2S)-3-(4′-Hydroxymethyl-biphenyl-4-yl)-2-methoxy-propionic acid ethylester

A mixture of(2S)-2-Methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acidethyl ester from Example 1, Step A (1 eq), tetrakis(triphenylphosphine)palladium(0) (0.03 eq), sodium carbonate (1.5 eq) and4-hydroxymethylphenylboronic acid (2 eq) in Toluene/Ethanol (20:1) wasrefluxed till the reaction is completed by TLC. The mixture was dilutedwith ethyl acetate, extracted and washed with water, NaHCO₃, sodiumtartrate and brine. The organic layer was concentrated to dryness andchromatographied to afford the title compound.

Step B

(2S)-3-[4′-(4-Benzoyl-phenoxymethyl)-biphenyl-4-yl]-2-methoxy-propionicacid

(2S)-3-(4′-Hydroxymethyl-biphenyl-4-yl)-2-methoxy-propionic acid ethylester from Step A, was treated with 4-hydroxybenzophenone under thestandard Mitsunobu coupling procedure B (THF). The product obtainedafter chromatography was hydrolyzed using the Standard Procedure C toget the title compound. ¹H-NMR (CDCl₃, 200.15 MHz): 7.86–7.73 (m, 4H),7.63–7.43 (m, 9H), 7.34–7.29 (m, 2H), 7.05 (d, 2H, J=9.1), 5.18 (s, 2H),4.06 (dd, 1H, J=7.3, 4.0), 3.42 (s, 3H), 3.20 (dd, 1H, J=14.5, 4.0),3.06 (dd, 1H, J=14.5, 7.3). MS (ES) for C₃₀H₂₆O₅ [M+H]⁺: 467.2, [M+Na]⁺:489.2.

Example 81(2S)-(1′R*,3′R*)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

Step A(1RS,3RS)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol

To a solution of rac-1,3-pentanediol (0.46 g, 4.5 mmol) in 23 mL of THFat 0° C. was added sodium hydride (0.18 g, 4.5 mmol, 60% oildispersion). The mixture was stirred at 0° C. for 1 h.Tert-butyldimethylsilyl chloride (0.678 g, 4.5 mmol) was added, and themixture was stirred overnight at room temperature. The mixture compoundswere concentrated and purified by silica gel chromatography (silica gel,hexanes/ethyl acetate 3:1) to give 0.682 g, of the title compound transand 0.157 g (6%) of the other cis isomer(1R*,3S*)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol. ¹H-NMR(200.15 MHz, CDCl₃): δ 4.48–4.36 (m, 2H), 2.19–1.89 (m, 2H), 1.85–1.79(m, 2H), 1.58–1.46 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H).

Step B

(1R*,3S*)-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-tert-butyl-dimethyl-silane

A solution of triphenylphosphine (0.195 g, 0.742 mmol) in 5 mL of dryTHF was treated at 0° C. with diethylazodicarboxylate (0.117 mL, 0.742mmol) and stirred for 20 min. A solution of(1R*,3R*)-3-(tert-butyldimethylsilanyloxy)cyclopentanol (0.146 g, 0.675mmol) and 4-phenyl phenol (0.126 g, 0.0.724 mmol) in 5 mL of dry THF wasadded to the solution, and the mixture was stirred at room temperatureovernight. The solution was concentrated under vacuum and purified bysilica gel chromatography (silica gel, hexanes/ethyl acetate 6:1,R_(f)0.66). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.58–7.29 (m, 7H); 6.93 (d,2H, J=8.92), 4.76–4.65 (m, 1H), 4.32–4.21 (m, 1H), 2.38 (qn, 1H, J=7.0),2.04–1.94 (m, 2H), 1.87–1.78 (m, 3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06(s, 3H).

Step C

(1R*,3S*)-3-(Biphenyl-4-yloxy)-cyclopentanol

(1R*,3S*)-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-tert-butyldimethylsilane(0.25 g, 0.67 mmol) was dissolved in 2 mL of THF and tetrabutylammoniumfluoride (0.67 mL, 1M in THF) and stirred at room temperature for 2hours. The solution was diluted with 15 mL of diethyl ether and washedwith 1N HCl (2×15 mL). The organic layer was dried (MgSO₄) andconcentrated. The residue was purified by silica gel chromatography(silica gel, hexanes/ethyl acetate 3:1, R_(f)0.09) to give the product(100%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.58–7.26 (m, 7H), 6.95 (d, 2H,J=8.9), 4.92–4.84 (m, 1H), 4.40–4.38 (m, 1H), 2.18–1.92 (m, 7H).

Step D

(2S)-(1′R*,2′R*)3-{4-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from (1R*,3S*)3-(Biphenyl-4-yloxy)-cyclopentanol and(2S)-2-methoxy-3-hydroxyphenylpropionic acid ethyl ester via theStandard Procedure A. Oily solid. ¹H-NMR (CDCl₃, 200.15 MHz): δ7.57–7.29 (m, 7H), 7.15 (d, 2H, J=8.6), 6.94 (d, 2H, J=8.9), 6.81 (d,2H, J=8.6), 4.99–4.91 (m, 2H), 3.99 (dd, 1H, J=7.3, 4.6), 3.41 (s, 3H),3.10 (dd, 1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.5, 7.3), 2.31 (t, 2H,J=4.8), 2.26–1.97 (m, 4H).

Example 82(2S)-(1′R*,3′S*)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

Step A(1R*,3S*)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol

The title compound was isolated from Example 81, Step A in a 6% yield.

Step B

(2S)-(1′R*,3′S*)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared starting from compound from Step A andfollowing the same procedure as in Example 81, to give the finalproduct. MS (ES) for C₂₇H₂₈O₅ [M+NH₄]⁺: 450.2, [M+Na]⁺: 455.23.

Example 83(2S)-(1′R*,3′R*)-2-Methoxy-3-{4-[3′-(4-phenoxy-phenoxy)-1′-cyclopentyloxy]-phenyl}-propionicacid

Step A(2S)-(1R*,3S*)-3-{4-[3′-(tert-Butyl-dimethyl-silanyloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid ethyl ester

A solution of triphenylphosphine (0.634 g, 2.23 mmol) in 15 mL of dryTHF was treated at 0° C. with diethylazodicarboxylate (0.2.45 mmol) andstirred for 20 min. A solution of(2S)-2-methoxy-3-hydroxyphenylpropionic acid ethyl (2.23 mmol) and1R*,3R*-tert-butyldimethylsylyloxy-cyclopentanol (0.245 mmol) in 5 mL ofdry THF was added to the solution, and the mixture was stirred at roomtemperature overnight. The mixture was concentrated under vacuum and theresidue was purified by silica gel chromatography.

Step B

(2S)-(1R*,3S*)-3-[4-(3′-Hydroxy-1′-cyclopentyloxy)-phenyl]-2-methoxy-propionicacid ethyl ester

The title compound was prepared folowing the Standard Procedure E togive the product.

Step C

(2S)-(1′R*,3′R*)-2-Methoxy-3-{4-[3′-(4-phenoxy-phenoxy)-1′-cyclopentyloxy]-phenyl}-propionicacid

(2S)-(1R*,3S*)-3-[4-(3′-Hydroxy-1′-cyclopentyloxy)-phenyl]-2-methoxy-propionicacid ethyl ester from Step A, was treated with 4-phenoxyphenol under thestandard Mitsounobu coupling procedure B (THF). The product obtainedafter chromatography was hydrolyzed using the standard hydrolysisprocedure C to get the title compound. ¹H-NMR (CDCl₃, 200.15 MHz):7.34–7.26 (m, 2H), 7.17–7.04 (m, 3H), 7.00–6.92 (m, 4H), 6.88–6.78 (m,4H), 4.94–4.89 (m, 2H), 3.99 (dd, 1H, J=7.3, 4.3), 3.41 (s, 3H), 3.10(dd, 1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.2, 7.3), 2.28 (t, 2H, J=4.8),2.21–1.89 (m, 4H). MS (ES) for C₂₇H₂₆O₆ [M+NH₄]⁺: 466.2, [M+Na]⁺: 471.2.

Example 84(2S)-(1′R*,3′R*)-3-{4-[3-(4-Benzoyl-phenoxy)-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared as manner analogous in Example 83,starting from (1R*,3R*)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanoland 4-hydroxy nezophenone. ¹H-NMR (CDCl₃, 200.15 MHz): 7.83–7.73 (m,4H), 7.56–7.42 (m, 3H), 7.15 (d, 2H, J=8.3), 6.92 (dd, 2H, J=7.0, 1.9),6.80 (d, 2H, J=8.6), 5.03–5.01 (m, 1H), 4.96–4.92 (m, 1H), 3.98 (dd, 1H,J=7.3, 4.6), 3.39 (s, 3H), 3.09 (dd, 1H, J=14.5, 4.6), 2.95 (dd, 1H,J=14.2, 7.3), 2.40–1.91 (m, 6H). MS (ES) for C₂₈H₂₈O₆ [M+H]⁺: 461.2,[M+Na]⁺: 483.2.

Example 85(2S)-(1′R*,3′R*)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-cyclopentyloxy]-phenyl}-propionicacid

The title compound was prepared as manner analogous in Example 83,starting from (1R*,3R*)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanoland 1-(4-Hydroxy-phenyl)-2-phenyl-ethanone. MS (ES) for C₂₉H₃₀O₆ [M+H]⁺:475.2, [+Na]⁺: 497.2. ¹H-NMR (CDCl₃, 200.15 MHz): 7.97 (d, 2H, J=8.9),7.32–7.23 (m, 5H); 7.15 (d, 2H, J=8.6), 6.91–6.77 (m, 4H), 5.01–4.91 (m,2H), 4.22 (s, 2H), 3.98 (dd, 1H, J=7.3, 4.6), 3.40 (s, 3H), 3.09 (dd,1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.5, 7.3), 2.33–1.92 (m, 6H).

Example 86(2S)-(1′R,3′S)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

Step A(1S*,3S*)-3-(Biphenyl-4-yloxy)-cyclopentanol

The title compound was prepared starting from(1R*,3S*)-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentanol of Example82, Step A, and running a Standard Mitsounobu coupling reaction B(toluene) with 4-phenylphenol. The product then was deprotected byStandard Procedure E to give the compound after purification bychromatography.

Step B

(1′S,2S,3′S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid3′-(biphenyl-4-yloxy)-1′-cyclopentyl ester

A mixture of (1S*,3S*)-3-(Biphenyl-4-yloxy)-cyclopentanol From Step A (1eq) with (S)-(−)-α-methoxy-α-(trifluoromethyl)-phenylacetic acid (1 eq),DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was stirred at 36° C.over night. The reaction mixture was cooled and concentrated to dryness.Reconstituted in ether and washed with HCl 1N, and NaHCO₃. Dry overMsSO4 and concentrated in vacuo to give a crude that was purify bysilica gel chromatography to give a diastereomeric mixture which wasseparated using chiral HPLC.

Step C

(1S,3S)-3-(Biphenyl-4-yloxy)-cyclopentanol

To a solution of compound from Step C in ethanol an excess of NaOH 1Nwas added and the mixture reaction was stirred at room temperature. Thesolution was concentrated in vacuo and diluted with brine. Extractedwith ether and concentrated to yield the title compound.

Step D

(2S)-(1′R,3*S)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared using the Standard Procedure forMitsounobu coupling-hydrolysis A in Toluene to give the final compound.MS (ES) for C₂₇H₂₈O₅ [M+NH₄]⁺: 450.2, [M+Na]⁺: 455.2. ¹H-NMR (CDCl₃,200.15 MHz): 7.56–7.28 (m, 6H), 7.15–7.08 (m, 3H), 6.95 (d, 2H, J=8.9),6.84–6.73 (m, 2H), 4.81–4.79 (m, 2H), 3.98 (dd, 1H, J=7.0, 4.3), 3.40(s, 3H), 3.10 (dd, 1H, J=14.2, 4.0), 2.95 (dd, 1H, J=14.2, 7.3),2.58–2.44 (m, 1H), 2.19–2.02 (m, 5H).

Example 87(2S)-(1′S,3′R)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

Step A(1′R,2S,3′R)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid3′-(biphenyl-4-yloxy)-1′-cyclopentyl ester

A mixture of (1S*,3S*)-3-(Biphenyl-4-yloxy)-cyclopentanol from Step A (1eq) with (S)-(−)-α-methoxy-α-(trifluoromethyl)-phenylacetic acid (1 eq),DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was stirred at 36° C.over night. The reaction mixture was cooled and concentrated to dryness.Reconstituted in ether and washed with HCl 1N, and NaHCO₃. Dry overMsSO4 and concentrated in vacuo to give a crude that was purify bysilica gel chromatography to give a diastereomeric mixture which wasseparated using chiral HPLC.

Step B

(2S)-(1′S,3′R)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared using the same procedures as in Example86, Steps C and D, to give the final compound. MS (ES) for C₂₇H₂₈O₅[M+NH₄]⁺: 450.2, [M+Na]⁺: 455.2. ¹H-NMR (CDCl₃, 200.15 MHz): 7.56–7.28(m, 6H), 7.15–7.08 (m, 3H), 6.95 (d, 2H, J=8.9), 6.84–6.73 (m, 2H),4.81–4.79 (m, 2H), 3.98 (dd, 1H, J=7.0, 4.3), 3.40 (s, 3H), 3.10 (dd,1H, J=14.2, 4.0), 2.95 (dd, 1H, J=14.2, 7.3), 2.58–2.44 (m, 1H),2.19–2.02 (m, 5H).

Example 88(2S)-(1′S,3′S)3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-(1′R*,2′R*)-3-{4-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid from 0, Step D, which was purified by chiral-HPLC to give thecorresponding enantiomer. MS (ES) for C₂₇H₂₈O₅ [M+NH₄]⁺: 450.2, [M+Na]⁺:455.2. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.57–7.29 (m, 7H), 7.15 (d, 2H,J=8.6), 6.94 (d, 2H, J=8.9), 6.81 (d, 2H, J=8.6), 4.99–4.91 (m, 2H),3.99 (dd, 1H, J=7.3, 4.6), 3.41 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.6),2.96 (dd, 1H, J=14.5, 7.3), 2.31 (t, 2H, J=4.8), 2.26–1.97 (m, 4H).

Example 89(2S)-(1′R,3′R)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-(1′R*,2′R*)3-{4-[3-(Biphenyl-4-yloxy)cyclopentyloxy]-phenyl}-2-methoxy-propionicacid from Example 81, Step D, which was purified by chiral-HPLC to givethe corresponding enantiomer. ¹H-NMR (CDCl₃, 200.15 MHz): d 7.57–7.29(m, 7H), 7.15 (d, 2H, J=8.6), 6.94 (d, 2H, J=8.9), 6.81 (d, 2H, J=8.6),4.99–4.91 (m, 2H), 3.99 (dd, 1H, J=7.3, 4.6), 3.41 (s, 3H), 3.10 (dd,1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.5, 7.3), 2.31 (t, 2H, J=4.8),2.26–1.97 (m, 4H). MS (ES) for C₂₇H₂₈O₅ [M+Na]⁺: 455.

Example 90(2S)-(1′R,3′S)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionicacid

Step A3-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanol

The title compound was prepared following the Standar Procedure D forthe monoprotection of diols, to give the product as a colorless oil.

Step B

[3-(Biphenyl-4-yloxy)-cyclohexyloxy]-tert-butyl-dimethyl-silane

The title compound was prepared using the Standard Procedure forMitsounobu coupling B (Toluene) to give the product as a colorless oil.MS (ES) for C₂₄H₃₄O₂Si: [M+H]⁺: 383.3.

Step C

3-(Biphenyl-4-yloxy)-cyclohexanol

The title compound was prepared by the Standard Procedure E for cleveagethe protected alcohols to give a mixture of the four isomers of thecompounds. The mixture was purified by silicagel chromatography to givethe corresponding two isomers (trans).(1S*,3S*)-3-(Biphenyl-4-yloxy)-cyclohexanol ¹H-NMR (CDCl3, 500.00 MHz):7.55 (d, J=7.3 Hz, 2H); 7.51 (d, J=8.5 Hz, 2H); 7.41 (t, J=7.9 Hz, 2H);7.30 (t, J=7.3 Hz, 1H); 6.97 (d, J=8.5 Hz, 2H); 4.74–4.72 (m, 1H);4.20–4.15 (m, 1H); 2.09–2.04 (m, 1H); 1.86–1.70 (m, 6H); 1.53–1.27 (m,3H)ppm and (cis)(1R*,3S)-3-(Biphenyl-4-yloxy)-cyclohexanol ¹H-NMR(CDCl₃, 500.00 MHz): 7.54 (d, J=7.6 Hz, 2H); 7.51 (d, J=8.5 Hz, 2H);7.41 (t, J=7.6 Hz, 2H); 7.30 (t, J=7.3 Hz, 1H); 6.97 (d, J=8.5 Hz, 2H);4.39–4.36 (m, 1H); 3.83–3.80 (m, 1H); 2.31 (d, J=12.3 Hz, 1H); 2.04–1.85(m, 4H); 1.72–1.34 (m, 10H)ppm.

Step D

(1R,3S)-(2S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid3-(biphenyl-4-yloxy)-1-cyclohexyl ester

A mixture of (1R*,3S*)-3-(Biphenyl-4-yloxy)-cyclohexanol from Step C (1eq) with (S)-(−)-α-methoxy-α-(trifluoromethyl)-phenylacetic acid (1 eq),DMAP (0.1 eq) and EDCI (1.2 eq) in dichloromethane was stirred at 36° C.over night. The reaction mixture was cooled and concentrated to dryness.Reconstituted in: ether and washed with HCl 1N, and NaHCO₃. Dry overMsSO₄ and concentrated in vacuo to give a crude that was purified bysilica gel chromatography to give a diastereomeric mixture which wasseparated using chiral HPLC

Step E

(1R,3S)-3-(Biphenyl-4-yloxy)-cyclohexanol

To a solution of compound from Step D in ethanol an excess of NaOH 1Nwas added and the mixture reaction was stirred at room temperature. Thesolution was concentrated in vacuo and diluted with brine. Extractedwith ether and concentrated to yield the title compound.

Step F

(2S)-(1′S,3′R)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared using the Standard Procedure forMitsounobu coupling-hydrolysis A in Toluene to give the final compound.¹H-NMR (CDCl₃, 200.15 MHz): 7.73–7.28 (m, 7H), 7.12 (dd, 2H, J=10.2,8.6), 7.00–6.93 (m, 1H), 6.86–6.73 (m, 2H), 4.34–4.19 (m, 2H), 3.98 (dd,1H, J=7.3, 4.3), 3.39 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.94 (dd, 1H,J=14.5, 7.3), 2.67–2.61 (m, 1H), 2.27–2.18 (m, 1H), 1.96–1.93 (m, 1H),1.71–1.54 (m, 1H), 1.46–1.37 (m, 3H).

Example 91(2S)-(1′S,3′R)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionicacid

Step A(1S,3R)-(2S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid3-(biphenyl-4-yloxy)-1-cyclohexyl ester

A mixture of (1R*,3S*)-3-(Biphenyl-4-yloxy)-cyclohexanol from Example90, Step C (1 eq) with(S)-(−)-α-methoxy-α-(trifluoromethyl)-phenylacetic acid (1 eq), DMAP(0.1 eq) and EDCI (1.2 eq) in dichloromethane was stirred at 36° C. overnight. The reaction mixture was cooled and concentrated to dryness.Reconstituted in ether and washed with HCl 1N, and NaHCO₃. Dry overMsSO₄ and concentrated in vacuo to give a crude that was purified bysilica gel chromatography to give a diastereomeric mixture which wasseparated using chiral HPLC.

Step B

(1S,3R)-3-(Biphenyl-4-yloxy)-cyclohexanol

The compound was prepared using the same procedure as in Example 90,Step E.

Step C

(2S)-(1′S,3′R)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared using the Standard Procedure forMitsounobu coupling-hydrolysis A in toluene to give the final compound.¹H-NMR (CDCl₃, 200.15 MHz): 7.73–7.28 (m, 7H), 7.12 (dd, 2H, J=10.2,8.6), 7.00–6.93 (m, 1H), 6.86–6.73 (m, 2H), 4.34–4.19 (m, 2H), 3.98 (dd,1H, J=7.3, 4.3), 3.39 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.94 (dd, 1H,J=14.5, 7.3), 2.67–2.61 (m, 1H), 2.27–2.18 (m, 1H), 1.96–1.93 (m, 1H),1.71–1.54 (m, 1H), 1.46–1.37 (m, 3H).

Example 92(2S)-(1′R,3′R)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionicacid

Step A(1R,3S)-(2S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid3-(biphenyl-4-yloxy)-1-cyclohexyl ester

A mixture of (1R*,3R*)-3-(Biphenyl-4-yloxy)-cyclohexanol (trans), fromExample 90, Step C (1 eq) with(S)-(−)-α-methoxy-α-(trifluoromethyl)-phenylacetic acid (1 eq), DMAP(0.1 eq) and EDCI (1.2 eq) in dichloromethane was stirred at 36° C. overnight. The reaction mixture was cooled and concentrated to dryness.Reconstituted in ether and washed with HCl 1N, and NaHCO₃. Dry overMsSO4 and concentrated in vacuo to give a crude that was purify bysilcagel chromatography to give a diastereomeric mixture which wasseparated using chiral HPLC.

Step B

(1R,3R)-3-(Biphenyl-4-yloxy)-cyclohexanol

The compound was prepared using the same procedure as in Example 90,Step E.

Step C

(2S)-(1′R,3′R)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared using the Standard Procedure forMitsounobu coupling-hydrolysis A in toluene to give the final compound.¹H-NMR (CDCl₃, 200.15 MHz): 7.57–7.27 (m, 7H), 7.13 (d, 2H, J=8.6), 6.96(dd, 2H, J=6.7, 2.1), 6.83 (d, 2H, J=8.9), 4.75–4.72 (m, 2H), 4.00–3.95(m, 1H), 3.38 (s, 3H), 3.09 (dd, 1H, J=14.8, 4.3), 2.94 (dd, 1H, J=14.5,7.5), 2.12–2.05 (m, 3H), 1.80–1.78 (m, 5H).

Example 93(2S)-(1′S,3′S)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionicacid

Step A(1S,3S)-(2S)-3,3,3-Trifluoro-2-methoxy-2-phenyl-propionic acid3-(biphenyl-4-yloxy)-1-cyclohexyl ester

A mixture of (1R*,3R*)-3-(Biphenyl-4-yloxy)-cyclohexanol (trans), fromExample 90, Step C (1 eq) with(S)-(−)-α-methoxy-α-(trifluoromethyl)-phenylacetic acid (1 eq), DMAP(0.1 eq) and EDCI (1.2 eq) in dichloromethane was stirred at 36° C. overnight. The reaction mixture was cooled and concentrated to dryness.Reconstituted in ether and washed with HCl 1N, and NaHCO₃. Dry overNaSO4 and concentrated in vacuo to give a crude that was purify bysilica gel chromatography to give a diastereomeric mixture which wasseparated using chiral HPLC.

Step B

(1S,3S)-3-(Biphenyl-4-yloxy)-cyclohexanol

The compound was prepared using the same procedure as in Example 90,Step E.

Step C

(2S)-(1′S,3′S)-3-{4-[3′-(Biphenyl-4-yloxy)-1′-cyclohexyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared using the Standard Procedure forMitsounobu coupling-hydrolysis A in toluene to give the final compound.¹H-NMR (CDCl₃, 200.15 MHz): 7.57–7.27 (m, 7H), 7.13 (d, 2H, J=8.6), 6.96(dd, 2H, J=6.7, 2.1), 6.83 (d, 2H, J=8.9), 4.75–4.72 (m, 2H), 4.00–3.95(m, 1H), 3.38 (s, 3H), 3.09 (dd, 1H, J=14.8, 4.3), 2.94 (dd, 1H, J=14.5,7.5), 2.12–2.05 (m, 3H), 1.80–1.78 (m, 5H).

Example 94(2S)-3-{1-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-methoxy-propionicacid

To a solution of (2S)-3-hydroxyphenyl-2-methoxy-propionic acid (7.30 g,37.2 mmol) in 40 mL of dry DMF was added tert-butyldimethylsilylchloride (11.80 g, 78.2 mmol) and imidazole (5.32 g, 78.2 mmol). Thesolution was stirred at room temperature overnight. Water (40 mL) wasadded, and the aqueous phase was extracted with hexanes (40 mL). Theorganic layer was washed with water (50 mL), dried (MgSO₄), andconcentrated. The crude material was dissolved in THF (20 mL), andsaturated NaHCO₃ solution (20 mL) was added. The resulting mixture wasstirred for 2 hours at room temperature. The aqueous layer was extractedwith ethyl acetate (40 mL), acidified to pH 3, and extracted again withethyl acetate (3×40 mL). The combined organic layers were washed withbrine (60 mL) and dried (MgSO4), and concentrated to a yellow oil (11.5g, 99%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.09 (d, 2H, J=8.3), 6.76 (d, 2H,J=8.6), 3.97 (dd, 1H, J=7.5, 4.3), 3.38 (s, 3H), 3.09 (dd, 1H, J=14.5,4.3), 2.93 (dd, 1H, J=14.2, 7.3), 0.97 (s, 9H), 0.18 (6H, s).

Step B

Preparation of(2S)-3-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-methoxy-propionicacid linked to Wang's Resin

The reaction was carried out in a polypropylene syringe equipped with apolypropylene frit. Wang's resin (1 eq, ca. 1.2 mmol/g resin) wassuspended in dichloromethane (0.05 M) and(2S)-3-[4-(tert-butyldimethylsilanyloxy)phenyl]-2-methoxypropionic acid(1.5 eq), disopropylcarbodiimide (2.0 eq), and a catalytic amount ofdimethylaminopyridine were added. The mixture was shaken at roomtemperature overnight. The reaction solvent was removed, and the resinwas washed sequentially with CH₂Cl₂ (2×), DMF (2×), CH₂Cl₂ (2×),methanol, and CH₂Cl₂ (2×). The resin was dried under vacuum for 5 hours.The resin was suspended in CH₂Cl₂ (0.05 M) and treated with aceticanhydride (5 eq) and a catalytic amount of dimethyaminopyridine for 2hours. The solvent was removed and the resin washed sequentially with amixture of 1:1 acetic acid/CH₂Cl₂ (3×), CH₂Cl₂ (2×), methanol, CH₂Cl₂(2×) and dried under vacuum overnight to give(2S)-3-[4-(tert-butyldimethylsilanyloxy)-phenyl]-2-methoxy-propionicacid linked to Wang's Resin.

Step C

Preparation of (2S)-3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid linkedto Wang's Resin

The reaction was carried out in a polypropylene syringe equipped with apolypropylene frit. To a suspension of(2S)-3-[4-(tert-butyldimethylsilanyloxy)-phenyl]-2-methoxy-propionicacid linked to Wang's Resin (1 eq) in dichloromethane (0.05 M) was addedtetrabutylammonium fluoride (ca 5 eq). The mixture was shaken at roomtemperature for 3 hours. The solvent was removed, and the resin waswashed sequentially with CH₂C₂ (2×), DMF (2×), CH₂Cl₂ (2×), is methanol,and CH₂Cl₂ (2×). The resin was dried under vacuum overnight to produce(2S) 3-(4-hydroxy-phenyl)-2-methoxy-propionic acid linked to Wang'sResin. Cleavage of 20 mg of the resin in TFA/CH₂Cl₂ 1:1 followed byevaporation of the solvent produced(S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid as an oil. ¹H-NMR(200.15 MHz, CDCl₃): δ 7.10 (d, 2H, J=8.6), 6.76 (d, 2H, J=8.6), 3.99(dd, 1H, J=7.0, 4.6), 3.41 (s, 3H), 3.10 (dd, 1H, J=14.5, 4.6), 2.95(dd, 1H, J=14.5, 7.5).

Step D

Preparation of (2S)-3-[4-(3-Hydroxy-propoxy phenyl]-2-methoxy-propionicacid linked to Wang's Resin

The title compound was prepared from(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid linked to Wang'sResin via Mitsunobu coupling (Standard Procedure F) to produce(2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin. Cleavage of 20 mg of the resin in TFA/CH₂Cl₂ 1:1 followedby evaporation of the solvent produced(2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid as anoil. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.16 (d, 2H, J=8.6), 6.82 (d, 2H,J=8.6), 4.56 (t, 1H, J=6.2), 4.09 (2H, dd, J=13.2, 5.9), 3.99 (dd, 1H,J=6.7, 4.0), 3.90 (1H, t, J=5.9), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.2,4.0), 2.96 (dd, 1H, J=14.2, 7.3), 2.22 (qn, 1H, J=5.9), 2.05 (qn, 1H,J=5.9).

Step E

(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin via the Mitsunobu coupling-cleavage from the resinprocedure (Standard Procedure G) to give 1.6 mg of a white solid (6%).¹H-NMR (200.15 MHz, CDCl₃): δ 7.82–7.72 (m, 4H), 7.57–7.43 (m, 3H), 7.14(d, 2H, J=8.8), 6.96 (d, 2H, J=8.8), 6.84 (d, 2H, J=8.8), 4.25 (t, 2H,J=6.0), 4.14 (t, 2H, J=6.0), 4.00 (dd, 1H, J=6.8, 4.6 Hz), 3.41 (s, 3H),3.10 (dd, 1H, J=14.1, 4.6), 2.97 (dd, 1H, J=14.1, 6.8), 2.28 (qn, 2H,J=6.0).

Example 95(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with4-hydroxybenzophenone and cleavage from the resin (Standard Procedure G)gave an oil (7%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.82–7.73 (m, 4H),7.19–7.10 (m, 4H), 6:96 (d, 2H, J=8.9), 6.84 (d, 2H, J=8.9), 4.25 (t,2H, J=6.0), 4.15 (t, 2H, J=6.0), 4.00 (dd, 1H, J=6.7, 4.6), 3.41 (s,3H), 3.10 (dd, 1H, J=14.1, 4.6), 2.97 (dd, dd, J=14.1, 6.8), 2.28 (qn,2H, J=6.0). MS (ES) for C₂₆H₂₅FO₆ [M+H]⁺: 453.2, [M+Na]⁺: 475.2.

Example 96(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with4-hydroxydiphenylmethane and cleavage from the resin (Standard ProcedureG) produced a white solid (5%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.29–7.13(m, 6H), 7.08 (d, 2H, J=8.9), 6.82 (d, 2H, J=8.6), 4.12 (t, 4H, J=6.2),3.97 (dd, 1H, J=6.6, 4.0), 3.39 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.0),2.95 (dd, 1H, J=14.2, 6.6), 2.22 (qn, 2H, J=6.2).

Example 97(2S)-2-Methoxy-3-{4-[3-(3-phenylamino-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with3-hydroxydiphenylamine and cleavage from the resin (Standard ProcedureG) gave an oily solid (4%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.31–6.81 (m,8H), 6.83 (d, 2H, J=8.6), 6.65–6.62 (m, 2H), 6.48 (dd, 1H, J=8.2, 2.1),4.12 (t, 4H, J=6.2), 3.99 (dd, 1H, J=7.0, 4.4), 3.40 (s, 3H), 3.10 (dd,1H, J=14.2, 4.4), 2.95 (dd, 1H, J=14.2, 7.0), 2.22 (qn, 2H, J=6.2).

Example 98(2S)-3-{4-[3-(4-Butyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with4-n-butylphenol and cleavage from the resin (Standard Procedure G) gavean oily solid (7%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.11 (dd, 4H, J=12.7,8.6), 6.82 (dd, 4H, J=8.6, 3.2), 4.12 (t, 4H, J=6.2), 3.97 (dd, 1H,J=7.7, 4.4), 3.38 (s, 3H), 3.30 (dd, 1H, J=14.5, 4.4), 2.94 (dd, 1H,J=14.5, 7.7), 2.54 (t, 2H, J=7.7), 2.23 (qn, 2H, J=6.2), 1.63–1.48 (m,2H), 1.42–1.24 (m, 2H), 0.91 (t, 3H, J=7.2).

Example 99(2S)-3-(4-{3-[4-(2-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with2-fluoro-4′-hydroxybenzophenone and cleavage from the resin (StandardProcedure G) gave an oily solid (7%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.81(dd, 2H, J=8.8, 1.3), 7.54–7.45 (m, 2H), 7.28–7.09 (m, 4H), 6.94 (d, 2H,J=8.6), 6.83 (d, 2H, J=8.6), 4.24 (t, 2H, J=6.2), 4.14 (t, 2H, J=6.2),3.98 (dd, 1H, J=7.0, 4.6), 3.40 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.6),2.96 (dd, 1H, J=14.2, 7.0), 2.28 (q, 2H, J=6.2).

Example 100(2S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with2-hydroxy-9-fluorenone and cleavage from the resin (Standard ProcedureG) gave an oily solid. ¹H-NMR (200.15 MHz, CDCl₃): 7.59 (d, 1H, J=7.0);7.43–7.37 (m, 3H); 7.26–7.13 (m, 4H); 6.98 (dd, 1H, J=8.1, 2.4); 6.85(d, 2H, J=8.6); 4.17 (qui, 4H, J=5.6); 3.99 (dd, 1H, J=7.0, 4.6); 3.40(s, 3H); 3.10 (dd, 1H, J=14.2, 4.6); 2.96 (dd, 1H, J=14.2, 7.0);2.32–2.23 (m, 4H) ppm.

Example 101(2S)-2-Methoxy-3-{4-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with2-methyl-5-benzothiazolol and cleavage from the resin (StandardProcedure G) to give an oily solid. ¹H-NMR (200.15 MHz, CDCl₃): 7.65 (d,1 H, J=8.9), 7.36–7.35 (m, 1 H), 7.16 (d, 2 H, J=8.9), 7.03 (dd, 1 H,J=8.9, 2.4), 6.86 (dd, 2 H, J=6.5, 1.9), 4.22 (t, 2 H, J=35.9), 4.18 (t,2 H, J=6.2), 4.01 (dd, 2 H, J=6.4, 5.4), 3.43 (s, 3 H), 3.14–2.94 (m, 2H), 2.87 (s, 3 H), 2.27 (qn, 2 H, J=6.2) ppm.

Example 102(2S)-2-Methoxy-3-{4-[3-(3-morpholin-4-yl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with3-(4-morpholino)phenol and cleavage from the resin (Standard ProcedureG) gave an oily solid. ¹H-NMR (200.15 MHz, CDCl₃): 7.32–7.23 (m, 1 H),7.14–7.10 (m, 2 H), 6.84–6.69 (m, 5 H), 4.14 (q, 4 H, J=5.6), 4.02–3.94(m, 5 H), 3.40 (s, 3 H), 3.33–3.28 (m, 4 H), 3.13–2.91 (m, 2 H), 2.23(qn, 2 H, J=5.9) ppm.

Example 103(2S)-3-{4-[3-(Biphenyl-2-yloxy)-propoxy]-phenoxy}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with2-phenylphenol and cleavage from the resin (Stand Procedure G) to givethe title compound. ¹H-NMR (200.15 MHz, CDCl₃): 7.51–7.43 (m, 2 H),7.38–7.29 (m, 5 H), 7.15–6.98 (m, 4 H), 6.79–6.72 (m, 2 H), 4.15 (t, 2H, J=5.9 Hz), 4.04–3.96 (m, 3 H), 3.39 (s, 3 H), 3.15–2.90 (m; 2 H),2.15 (qn, 2 H, J=5.9 Hz) ppm.

Example 104(2S)-3-{4-[3-(4-Cyclopentyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with4-cyclopentylphenol and cleavage from the resin (Standard Procedure G)gave an oily solid.

Example 105(2S)-3-{4-[3-(4-Cyano-3-fluoro-phenoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with2-fluoro-4-hydroxybenzonitrile and cleavage from the resin (StandardProcedure G) gave an oily solid.

Example 106(2S)-3-{4-[3-(2,4-Difluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with2,4-difluorophenol and cleavage from the resin (Standard Procedure G)gave an oily solid.

Example 107(2S)-2-Methoxy-3-{4-[3-(4-trifluoromethyl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with4-trifluoromethylphenol and cleavage from the resin (Standard ProcedureG) gave an oily solid.

Example 108(2S)-2-Methoxy-3-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin Example 94, Step D) via Mitsunobu coupling with3-trifluoromethylphenol and cleavage from the resin (Standard ProcedureCG) gave an oily solid.

Example 109(2S)-2-Methoxy-3-{4-[3-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with6-hydroxy-1,2,3,4-tetrahydronaphtalenone and cleavage from the resin(Standard Procedure G) gave an oily solid.

Example 110(2S)-3-{4-[3-(3,5-Difluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with3,5-difluorophenol and cleavage from the resin (Standard Procedure G)gave an oily solid.

Example 111(2S)-3-{4-[3-(Isoquinolin-5-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with5-hydroxyisoquinolyne and cleavage from the resin (Standard Procedure G)gave an oily solid.

Example 112(2S)-2-Methoxy-3-{4-[3-(4-trifluoromethoxy-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with4-trifluoromethoxyphenol and cleavage from the resin (Standard ProcedureG) gave an oily solid.

Example 113(2S)-3-{4-[3-(4-Fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with4-fluorophenol and cleavage from the resin (Standard Procedure G) gavean oily solid.

Example 114(2S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling withbenzyl-4-hydroxyphenylketone and cleavage from the resin (StandardProcedure G) gave an oily solid.

Example 115(2S)-2-Methoxy-3-(4-{3-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-propoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with4-cumylphenol and cleavage from the resin (Standard Procedure G) gave anoily solid.

Example 116(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with7-hydroxyflavone and cleavage from the resin (Standard Procedure G) gavean oily solid.

Example 1174-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acidbenzyl ester

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with benzyl4-hydroxybenzoate and cleavage from the resin (Standard Procedure G)gave an oily solid.

Example 118(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-6-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with6-hydroxyflavone and cleavage from the resin (Standard Procedure G) gavean oily solid.

Example 119(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-6-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with6-hydroxyflavanone and cleavage from the resin (Standard Procedure G)gave an oily solid.

Example 120(2S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-chroman-7-yloxy-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin Example 94, Step D) via Mitsunobu coupling with7-hydroxyflavanone and cleavage from the resin (Standard Procedure G)gave an oily solid.

Example 121(2S)-2-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked toWang's Resin (Example 94, Step D) via Mitsunobu coupling with4-(4-trifluoromethyl)phenoxyphenol and cleavage from the resin (StandardProcedure G) gave an oily solid.

Example 122(2S)-3-{4-[2-(4-benzoyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionicacid

Step A2-(tert-Butyl-dimethyl-silanyloxy)-ethanol

To a solution of ethylene glycol (1.00 g, 16.1 mmol) in THF (80 mL) wasadded NaH (0.65 mg, 16.1 mmol, 60% oil dispersion) at 0° C. The reactionwas stirred 1 hour, tert-butyldimethylsilyl chloride (2.35 g, 16.1 mmol)was added, and the reaction mixture was allowed to warm to roomtemperature. After 3 hours at room temperature, Na₂CO₃ saturatedsolution (80 mL) was added, and the aqueous layer was extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater (80 mL) and brine (80 mL), dried over (MgSO₄), and concentratedunder vacuum. The reaction crude was purified by silica gel columnchromatography (silica gel, hexanes/ethyl acetate, 2:3) to produce 1.93g, (85%) of a yellow oil. ¹H-NMR (200.15 MHz, CDCl₃): δ 3.74–3.59 (m,4H), 0.91 (s, 9H), 0.08 (s, 6H).

Step B

Preparation of(2S)-3-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-2-methoxy-propanoicacid linked to Wang's Resin

The title compound was prepared from(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid linked to Wang'sResin (Example 94, Step D) via the Mitsunobu coupling procedure with2-(tert-butyldimethylsilanyloxy)ethanol (Standard Procedure B).

Step C

Preparation of (2S)-3-[4-[2-Hydroxyethoxy]-phenyl}-2-methoxy-propanoicacid linked to Wang's Resin

The title compound was prepared from3-{4-[2-tert-butydimethylsilanyloxy)ethoxy]-phenyl}-2-methoxy-propanoicacid linked to Wang's Resin when treated with tetrabutylammoniumfluoride in THF as described in Standard Procedure E. Cleavage of 20 mgof the resin in TFA/CH₂Cl₂ (1:1) followed by evaporation of the solventproduced (2S)-3-[4-[2-hydroxy-ethoxy]-phenyl}-2-methoxy-propanoic acidas an oil. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.16 (d, 2H, J=8.6), 6.85 (d,2H, J=8.9), 4.09–3.93 (m, 5H), 3.41 (s, 3H), 3.11 (dd, 1H, J=14.5, 4.0),2.97 (dd, 1H, J=14.5, 7.2).

Step D

(2S)-3-{4-[2-(4-Benzoyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid linked to Wang'sResin via Mitsunobu coupling Standard Procedure G. Cleavage from theresin gave an oily solid. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.84–7.72 (m,4H), 7.60–7.41 (m, 3H), 7.18 (d, 2H, J=8.6), 6.99 (d, 2H, J=8.9), 6.87(d, 2H, J=8.7), 4.43–4.32 (m, 4H), 3.96 (dd, 1H, J=7.5, 4.6), 3.65 (s,3H), 3.09 (dd, 1H, J=14.2, 4.2), 2.95 (dd, 1H, J=14.2, 7.8)ppm.

Example 123(2S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

Step A(Biphenyl-4-yloxy)-acetic acid ethyl ester

To a solution of 4-phenylphenol (1.02 g, 5.99 mmol) in 10 mL of DMF at−20° C. was added sodium hydride (0.24 g, 5.99 mmol, 60% oil dispersion)and the mixture stirred at 0° C. for 30 min. 2-bromoethyl acetate (0.66mL, 5.99 mmol) was added and the mixture stirred at room temperatureovernight. The solution was diluted with water (50 mL) and extractedwith diethyl ether (3×20 mL). The combined extracts were washed withwater (4×20 mL), dried (MgSO₄) and concentrated under vacuum. 0.63 g(41%). ¹H-NMR (CDCl₃, 200.15 MHz): 7.57–7.56 (m, 4H), 7.45–7.26 (m, 3H),6.98 (dd, 2H, J=6.4, 2.1), 4.66 (s, 2H), 4.29 (q, 2H, J=7.3), 1.31 (t,5H, J=7.3) ppm.

Step B

2-(Biphenyl-4-yloxy)-ethanol

To a solution of (Biphenyl-4-yloxy)-acetic acid ethyl ester (0.63 g,2.46 mmol) in dry toluene (15 mL) at −78° C. was added DIBAL-H 1M intoluene (4.92 mL, 4.92 mmol). The solution was stirred at −78° C. for 1hour, warmed to room temperature and quenched with mixture of a solutionof sodium tartrate in water and ethyl acetate for 1 hour. The layerswere separated and the aqueous phase further extracted with ethylacetate. The combined organic layers were dried (MgSO₄), concentratedunder vacuum and the residue purified bu column chromatography (silicagel, hexanes/Ethyl acetate 4:1, R_(f)0.1), 48%. ¹H-NMR (CDCl₃, 200.15MHz): 7.58–7.26 (m, 8H); 7.00 (d, 2H, J=8.6), 4.14 (t, 2H, J=4.6),4.02–3.98 (m, 2H); 2.04 (t, 1H, J=5.4).

Step C

(2S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from 2-(Biphenyl-4-yloxy)-ethanol and(2S)-2-Methoxy-3-hydroxyphenyl propionic acid ethyl ester using thegeneral procedure A (34%). ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.55–7.49 (m,4H); 7.43–7.35 (m, 2H); 7.29 (d, 1H, J=7.3); 7.15 (d, 2H, J=8.8); 7.00(d, 2H, J=8.8); 6.88 (d, 2H, J=8.8); 4.36–4.29 (m, 4H); 3.98 (dd, 1H,J=7.0, 4.4); 3.39 (s, 3H); 3.10 (dd, 1H, J=14.3, 4.4); 2.95 (dd, 1H,J=14.3, 7.3)ppm. MS (ES) for C₂₄H₂₄O₅ [M+NH₄]⁺: 410.

Example 124(2S)-3-{4-[2-(Biphenyl-4-yloxy)-acetyl]-phenyl}-2-methoxy-propionic acid

Step A(2S)-3-(4-Ethynyl-phenyl)-2-methoxy-propionic acid ethyl ester

To a solution of(2S)-2-Methoxy-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acidethyl ester (0.100 g, 0.29 mmol) (Example 1, Step A) in 10 mL ofdegassed piperidine, was added (trimethylsilyl)acetylene (99,6 mg, 1.015mmol), tetrakis(triphenylphosphine) Palladium (0) (0.017 g, 0.015 mmol),triphenylphosphine (7.7 mg, 0.029 mmol) and cooper (I) Iodide (5.5 mg,0.029 mmol). The solution was stirred for 2 hours at 120° C. and thencooled to room temperature. The solvent was evaporated under vacuum. Theresidue was dissolved in dry THF and 0.4 mL of a solution oftetrabutylamonium fluoride (1.0 M in THF) and 0.02 mL of water wereadded. The mixture was stirred at room temperature for 5 min. Thesolvent was evaporated under vacuum and the residue partitioned betweenwater (20 ml) and diethyl ether (20 mL). The layers were separated andthe aqueous solution extracted twice with 20 ml of diethylether. Thecombined organic layers were washed with 10% Na₂CO₃ (6×20 ml) and brine(20 ml) and dried (MgSO₄). Concentration produced a yellow oil (38 mg,56%) ¹H-NMR (200.15 MHz, CDCl₃): δ 7.95 (d, 1H, J=7.3), 7.25 (d, 1H,J=7.3), 4.18 (q, 2H, J=7.0), 3.97 (dd, 1H, J=7.3, 5.6), 3.36 (s, 3H),3.05 (d, 1H, J=5.3), 3.02 (d, 1H, J=2.4 Hz), 1.22 (t, 3H, J=7.25).

Step B

(2S) 3-(4-Acetyl-phenyl)-2-methoxy-propionic acid ethyl ester

To (2S)-3-(4-Ethynyl-phenyl)-2-methoxy-propionic acid ethyl ester (36Mg, 0.15 mmol) (Example 29, Step A) were added 4 ml of formic acid. Thesolution was stirred for 1 hour at 100° C. and then cooled to roomtemperature. The mixture was taken up with methylene chloride and thesolution was washed with water, sodium carbonate, and water, dried(MgSO₄) and the solvent was evaporated under vacuum. Obtained a brownliquid (0.035 g, 95%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.43 (d, 1H, J=73),7.12 (d, 1H, J=7.3), 4.18 (q, 2H, J=7.0), 3.97 (dd, 1H, J=7.3, 5.6),3.32 (s, 3H), 3.06 (s, 1H), 3.03 (d, 1H, J=2.4 Hz), 2.56 (s, 2H), 1.22(t, 3H, J=7.25).

Step C

(2S) 3-[4-(2-Bromo-acetyl)-phenyl]-2-methoxy-propionic acid ethyl ester

Powdered cupric bromide (62 mg, 0.28 mmol) was added portionwise to asolution of (2S)-3-(4-Acetyl-phenyl)-2-methoxy-propionic acid ethylester (35 mg, 0.14 mmol) in CHCl₃ (5 ml) and ethyl acetate (5 mL). Thesolution was stirred for 1 hour at 65° C. and then cooled to roomtemperature. The mixture was filtered and the solvent evaporated undervacuum. The residue was purified by chromatography (silica gel,hexanes/Ethyl Ether 8:2, R_(f)0.20) to produce a colorless oil (25 mg,54%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.935 (d, 1H, J=7.3), 7.38 (d, 1H,J=7.3), 4.50 (s, 2H), 4.12 (q, 2H, J=7.0), 3.97 (dd, 1H, J=7.3, 5.6),3.38 (s, 3H), 3.10 (s, 1H), 3.06 (d, 1H, J=2.4 Hz), 1.22 (t, 3H,J=7.25).

Step D

(2S)-3-{4-[2-(Biphenyl-4-yloxy)-acetyl]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from a solution of(2S)-3-[4-(2-Bromo-acetyl)-phenyl]-2-methoxy-propionic acid ethyl ester(25 mg, 0.076 mmol) in acetonitrile (5 ml). 4-phenylphenol (29 mg, 0.152mmol) and K₂CO₃ (31,5 mg, 0.23 mmol) were added. The solution wasstirred for 30 min at 80° C. and then cooled to room temperature. Themixture was concentrated to dryness under vacuum and chromatographed insilica gel (hexanes/Ethyl ether 8:2 to 7:3). Fractions corresponding tothe coupled compound were collected (R_(f)0.27) and concentrated todryness. The mixture thus obtained was dissolved in 4 mL of NaOH 1N and12 mL of Methanol and stirred at room temperature until TLC indicatesthe disappearance of starting material. The methanol was eliminatedunder vacuum and the aqueous solution diluted with 20 mL of brine andwashed with diethyl ether (3×15 mL). The aqueous phase was acidulatedwith HCl 1N (until pH 3); extracted with ethyl acetate (3×15 mL) and theorganic layer dried (MgSO₄) and concentrated under vacuum. Obtained acolorless oil (9.6 mg, 32%). ¹H-NMR (200.15 MHz; CDCl₃): δ 7.96 (d, 2H,J=8.4), 7.55–7.23 (m, 9H), 6.99 (d, 2H, J=8.8), 5.26 (s, 2H), 4.03 (dd,1H, J=7.3, 5.6), 3.39 (s, 3H), 3.22 (dd, 1H, J=14.3, 5.5), 3.03 (dd, 1H,J=14.3, 7.2).

Example 125(2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxy)-acetyl]-phenyl}-propionicacid

The title compound was prepared from a solution of(2S)-3-[4-(2-Bromo-acetyl)-phenyl]-2-methoxy-propionic acid ethyl ester(0.076 mmol) from Example 124, Step C in acetonitrile (5 ml).4-phenoxyphenol (0.152 mmol) and K₂CO₃ (0.23 mmol) were added. Thesolution was stirred for 30 min at 80° C. and then cooled to roomtemperature. The mixture was concentrated to dryness under vacuum andchromatographed in silica gel (hexanes/Ethyl ether 8:2 to 7:3).Fractions corresponding to the coupled compound were collected (R_(f):0.27) and concentrated to dryness. The mixture thus obtained wasdissolved in 4 mL of NaOH 1N and 12 mL of Methanol and stirred at roomtemperature until TLC indicates the disappearance of starting material.The methanol was eliminated under vacuum and the aqueous solutiondiluted with 20 mL of brine and washed with diethyl ether (3×15 mL). Theaqueous phase was acidulated with HCl 1N (until pH 3); extracted withethyl acetate (3×15 mL) and the organic layer dried (MgSO₄) andconcentrated under vacuum. Obtained a colourless oil. ¹H-NMR (200.15MHz, CDCl₃): 7.96 (d, 2H, J=8.4), 7.55–7.33 (m, 5H), 7.04–6.83 (m, 6H),5.24 (s, 2H), 4.08 (dd, 1H, J=7.4, 4.4), 3.40 (s, 3H), 3.22 (dd, 1H,J=14.3, 4.4), 3.15 (dd, 1H, J=14.3, 7.2).

Example 126(2S)-3-{4-[2-(4-Benzoyl-phenoxy)-acetyl]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from a solution of (2S)3-[4-(2-Bromo-acetyl)-phenyl]-2-methoxy-propionic acid ethyl ester(0.076 mmol) from Example 124, Step C in acetonitrile (5 ml).4-hydroxybenzophenone (0.152 mmol) and K₂CO₃ (0.23 mmol) were added. Thesolution was stirred for 30 min at 80° C. and then cooled to roomtemperature. The mixture was concentrated to dryness under vacuum andchromatographed in silica gel (hexanes/Ethyl ether 8:2 to 7:3).Fractions corresponding to the coupled compound were collected(R_(f)0.27) and concentrated to dryness. The mixture thus obtained wasdissolved in 4 mL of NaOH 1N and 12 mL of Methanol and stirred at roomtemperature until TLC indicates the disappearance of starting material.The methanol was eliminated under vacuum and the aqueous solutiondiluted with 20 mL of brine and washed with diethyl ether (3×15 mL). Theaqueous phase was acidulated with HCl 1N (until pH 3); extracted withethyl acetate (3×15 ml) and the organic layer dried (MgSO₄) andconcentrated under vacuum. Obtained a colorless oil. ¹H-NMR (200.15 MHz,CDCl₃): 7.96–7.71 (m, 6H), 7.57–7.46 (m, 5H), 6.97 (d, 2H, J=8.1), 5.35(s, 2H), 4.08 (dd, 1H, J=7.4, 4.2), 3.26 (s, 3H), 3.20 (dd, 1H, J=14.1,4.1), 3.09 (dd, 1H, J=14.1, 7.2).

Example 127(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propyl]-phenyl}-2-methoxy-propionic acid

The title compound was prepared as follows: (2S)3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionic acid(0, Step C) (0.0325 g, 0.08 mmol) was dissolved in methanol (10 mL).Palladium 10% an activated carbon (0.004 g, 0.004 mmol) was added andthe solution saturated with hydrogen (1 Atm) and stirred for 5 hours.The mixture was filtered through a pad of celite and concentrated undervacuum. The residue was purified by column chromatography (silica gel,hexanes/Ethyl acetate-Acetic acid 50:50:1, R_(f)0.23) (85%). ¹H-NMR(CDCl₃, 200.15 MHz): δ 7.56–7.24 (m, 11H), 6.94 (d, 2H, J=8.8),4.02–3.95 (m, 3H), 3.38 (s, 3H), 3.11 (dd, 1H, J=14.3, 4.4), 2.98 (dd,1H, J=14.3, 7.3), 2.79 (t, 2H, J=8.1), 2.16–2.03 (m, 3H). MS (ES) forC₂₅H₂₆O₄ [M+NH₄]⁺: 408.2, [M+Na]⁺: 413.2.

Example 128(2S)-3-{4-[4-(Biphenyl-4-yloxy)-butyl]-phenyl}-2-methoxy-propionic acid

Step A(2S)-3-[4-(4-Hydroxy-butyl)-phenyl]-2-methoxy-propionic acid ethyl ester

(2S)-3-[4-(3-Hydroxy-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethylester (0.294 g, 1.06 mmol) was dissolved in ethyl acetate (50 mL).Palladium 10% on activated carbon (0.057 g, 0.05 mmol) was added and thesolution saturated with hydrogen (1 Atm) and stirred for 2 hours. Themixture was filtered through a pad of celite and concentrated undervacuum. (100%). ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.12 (dd, 4H, J=11.3,8.6), 4.17 (q, 2H, J=7.0), 3.94 (dd, 1H, J=7.0, 6.2), 3.65 (t, 2H,J=5.9); 3.35 (s, 3H), 3.00 (s, 1H), 2.97 (s, 1H), 2.61 (t, 2H, J=7.3),1.73–1.60 (m, 4H), 1.22 (t, 3H, J=7.0).

Step B

(2S)-3-{4-[4-(Biphenyl-4-yloxy)-butyl]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(4-Hydroxy-butyl)-phenyl]-2-methoxy-propionic acid ethyl esterand 4-phenylphenol following the Standard Procedure ofcoupling-hydrolysis A. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.55–7.23 (m, 7H);7.14 (d, 4H, J=1.1); 6.93 (d, 2H, J=8.4); 4.02–3.96 (m, 3H); 3.37 (s,3H); 3.11 (dd, 1H, J=14.3, 4.4); 2.97 (dd, 1H, J=14.3, 7.3); 2.66 (t,2H, J=7.0); 1.83–1.80 (m, 4H). MS (ES) for C₂₆H₂₈O₄ [M+NH₄]⁺: 422.2,[M+Na]⁺: 427.2.

Example 129(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentyl]-phenyl}-2-methoxy-propionic acid

The title compound was prepared as follows:(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid from Example 21 (0.08 mmol) was dissolved in methanol (10 mL).Palladium 10% on activated carbon (0.004 g, 0.004 mmol) was added andthe solution saturated with hydrogen (1 Atm) and stirred for 5 hours.The mixture was filtered through a pad of celite and concentrated undervacuum. The residue was purified by column chromatography. MS (ES) forC₂₇H₃₀O₄ [M−H]⁻: 417.3.

Example 130 3-{4-[3-(4-Benzoyl-phenoxy-propoxy]-3-methoxy-propionic acid

Step A3-(4-Benzyloxy-3-methoxy-phenyl)-3-hydroxy-2-methoxy-propionic acidmethyl ester

A solution of 4-benzyloxy-3-methoxy-benzaldehyde (0.44 g, 1.92 mmol) andmethyl methoxyacetate (0.19 mL, 1.92 mmol) in THF (10 mL) at −78° C. wasadded dropwise to sodium bis(trimethylsilyl)amide (20 mL, 2.11 mmol, 1Nin THF) at −78° C. The reaction mixture was stirred for 3 h and quenchedwith 1N HCl (5 mL). The mixture was allowed to warm to room temperature,diluted with water (15 mL), and extracted with ethyl acetate (3×15 mL).The combined organic layers were dried (MgSO₄) and concentrated. Theresidue was purified by silica gel column chromatography (silica gel,hexanes/ethyl acetate, 1:1) to produce3-(4-benzyloxy-3-methoxy-phenyl)-3-hydroxy-2-methoxy-propionic acidmethyl ester as an oil (350 mg, 52%); ¹H-NMR (200.15 MHz, CDCl₃): δ7.45–7.20 (m, 5H), 6.9 (s, 1H), 6.8 (b, 2H), 5.1 (s, 2H), 4.90–4.80 (m,1H), 4.10 (m, 1H), 3.90 (s, 3H), 3.65 (s, 3H), 3.31 (s, 3H), 3.10–2.96(m, 1H).

Step B

3-(4-Hydroxy-3-methoxy-phenyl-2-methoxy-propionic acid methyl ester

Trifluoroacetic anhydride (0.62 mL, 4.36 mmol) and triethylamine (0.62mL, 4.36 mmol) were added to a solution of3-(4-benzyloxy-3-methoxy-phenyl)-3-hydroxy-2-methoxy-propionic acidmethyl ester (1.01 g, 2.91 mmol) in methylene chloride (30 mL) at 0° C.The resulting mixture was stirred for 4 hours at room temperature andwas concentrated under vacuum. The residue was dissolved in ethylacetate (30 mL), and 10% palladium on carbon (0.3 g) was added to thesolution. The mixture was stirred under hydrogen pressure (4 atm) for 16hours. The mixture was filtered through Celite and concentrated undervacuum. The residue was purified by silica gel column chromatography(silica gel, hexanes/ethyl acetate 7:3) to produce3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid methyl ester asan oil (598 mg, 86%). ¹H-NMR (200.15 MHz, CDCl₃): δ 6.80 (d, 1H, J=7.8),6.7 (s, 1H), 6.62 (d, 1H, J=7.8), 3.96 (dd, 1H, J=7.8, 4.0), 3.80 (s,3H), 3.68 (s, 3H), 3.30 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.91 (dd,1H, J=14.2, 7.8).

Step C

3-(4-Hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid

A 1N aqueous lithium hydroxide solution was added to a solution of3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid methyl ester(280 mg, 1.17 mmol) in THF at room temperature, and the reaction mixturestirred overnight. The aqueous phase was extracted with ethyl acetate(20 mL), acidified to pH 2, and extracted with ethyl acetate (3×15 mL).The later organic layers were combined and washed with water (15 mL) andbrine (10 mL), dried (MgSO4), filtered, and concentrated under vacuum toproduce 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid as anoil (183 mg, 74%). ¹H-NMR (250.13 MHz, CDCl₃): δ 6.83 (1H, d, J=7.8),6.74 (1H, s), 6.72 (1H, d, J=7.8), 3.99 (1H dd, J=7.8, 4.0), 3.85 (s,3H), 3.40 (s, 3H), 3.09 (1H, dd, J=14.2, 4.0), 2.91 (1H dd, J=14.2,7.8).

Step D

3-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phenyl)-2-methoxy-propionicacid

To a solution of 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid(1.02 g, 4.87 mmol) in CH₂Cl₂-DMF (20 mL=10:1) was addedtert-butyl-dimethylsilyl chloride (1.75 g, 11.68 mmol) and imidazole(0.70 g, 10.24 mmol). The resulting solution was stirred at roomtemperature overnight. Water (15 mL) was added, and the aqueous phasewas extracted with hexanes (30 mL). The hexanes layer was washed withwater (10 mL), dried (MgSO₄), filtered, and concentrated. The crudeproduct was dissolved in ethyl acetate (10 mL), and a saturated solutionof K₂CO₃ (5 mL) was added. The resulting mixture was stirred for 2 hoursat room temperature. The aqueous layer was extracted with ethyl acetate(10 mL), acidified to pH 3, and extracted again with ethyl acetate (3×10mL). The later organic layers were combined and washed with brine (20mL), dried (MgSO4), and concentrated to a yellow oil (1.2 g, 77%).¹H-NMR (200.15 MHz, CDCl₃): δ 6.78–6.67 (m, 3H), 3.96 (dd, 1H, J=7.8,4.0), 3.78 (s, 3H), 3.35 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.0), 2.91 (dd,1H, J=14.2, 7.8), 0.98 (s, 9H), 0.13 (6H, s).

Step E

Preparation of3-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-2-methoxy-propionicacid linked to Wang's Resin

The title compound was prepared following the procedure as in Example95, Step B.

Step F

Preparation of 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acidlinked to Wang's Resin

The title compound was prepared following the procedure as in Example95, Step C.

Step G

Preparation of3-[4-(3-hydroxy-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acidlinked to Wang's Resin.

The title compound was prepared from3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid linked to Wang'sResin via Mitsunobu coupling (Standard Procedure F) to produce3-[4-(3-hydroxy-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acidlinked to Wang's Resin.

Step H

3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-(4-(3-hydroxy-propoxy)-3-methoxy-phenyl)-2-methoxy-propionic acidlinked to Wang's Resin via the Mitsunobu coupling-cleavage from theresin procedure (Standard Procedure G) to produce an oily solid (4%).¹H-NMR (200.15 MHz, CDCl₃): δ 7.81–7.72 (m, 4H), 7.57–7.43 (m, 3H), 6.96(d, 2H, J=8.9), 6.81–6.73 (m, 3H), 4.28 (t, 2H, J=6.2), 4.20 (t, 2H,J=6.2), 4.01 (dd, 1H, J=7.0, 4.6), 3.83 (s, 3H), 3.42 (s, 3H), 3.09 (dd,1H, J=14.5, 4.0), 2.97 (dd, 1H, J=14.5, 7.0), 2.33 (qn, 2H, J=6.2).

Example 1313-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-3-methoxy-phenyl-2-methoxy-propionicacid

The title compound was prepared from3-(4-(3-hydroxy-propoxy)-3-methoxy-phenyl)-2-methoxy-propionic acidlinked to Wang's Resin via the Mitsunobu coupling-cleavage from theresin procedure (Standard Procedure G) to produce an oily solid (4%).¹H-NMR (200.15 MHz, CDCl₃): δ 7.83–7.74 (m, 4H), 7.15 (t, 2H, J=8.6 Hz),6.96 (d, 2H, J=8.6), 6.85–6.74 (m, 3H), 4.28 (t, 2H, J=6.2), 4.20 (t,2H, J=6.2), 4.01 (dd, 1H, J=7.0, 4.6), 3.84 (s, 3H), 3.42 (s, 3H), 3.10(dd, 1H, J=14.2, 4.6), 2.97 (dd, 1H, J=14.2, 7.0), 2.33 (qn, 2H, J=6.2).

Example 1323-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid

Step A3-(4-Hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid ethyl ester

To a solution of3-[4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-2-methoxy-propionicacid (356 mg, 1.05 mmol) in absolute ethanol (8 mL) was addedconcentrated sulfuric acid (0.033 mL, 0.63 mmol). The reaction mixturewas allowed to stir at room temperature for 17 hours. The solution wasconcentrated under vacuum, and water (10 mL) and solid NaHCO₃ were addedto neutralize the residue. The aqueous phase was extracted with ethylacetate (2×10 mL). The combined organic layers were washed with water(20 mL) and brine (20 mL), dried (MgSO4), filtered, and concentrated toproduce 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acid ethylester (260 mg, 98%). ¹H-NMR (200.15 MHz, CDCl₃): δ 6.83 (d, 1H, J=8.1Hz), 6.76–6.69 (m, 2H), 4.19 (q, 2H, J=7.3 Hz), 3.97–3.90 (m, 1H), 3.87(s, 3H), 3.36 (s, 3H), 2.96–2.92 (m, 2H), 1.25 (t, 3H, J=7.3 Hz).

Step B

[1,3,2]Dioxathiane 2,2-dioxide

To a solution of 1,3-propanodiol (30 g, 394 mmol) in CCl₄ (278 mL) wasadded thionyl chloride (36 mL, 491 mmol) via syringe. The resultingmixture was heated at reflux for 1.5 h and was cooled to 0° C. toevaporate the solvent under vacuum. The residue was dissolved in amixture of CCl₄/CH₃CN/H₂O (2:2:3=500 mL) and cooled to 0° C. Rutheniumtrichloride trihydrate (0.556 g, 2.68 mmol) was added, followed byaddition of solid NaIO₄ (14.35 g, 197 mmol). The mixture was stirred atroom temperature for 1 h, H₂O (1 L) was added, and the aqueous phase wasextracted with diethyl ether (4×300 mL). The combined organic layerswere washed with brine (2×100 mL), dried (MgSO4), and filtered through apad of silica gel to remove the ruthenium salts. The solvent wasevaporated and hexanes (200 mL) was added to the resulting oil. Aftercooling, a gray solid precipitated. The solid was filtered and washedwith hexanes. Recrystallization from hexanes/ether yielded a white,crystalline solid (18.15 g, 33%). ¹H-NMR (200.15 MHz, CDCl₃): δ 4.73 (t,4H, J=5.6), 2.13 (qn, 2H, J=5.6).

Step C

3-(Biphenyl-4-yloxy)-propan-1-ol

A solution of 4-phenylphenol (4.9 g, 29.0 mmol) and potassiumtert-butoxide (3.64 g, 30.3 mmol) in THF (100 mL) was stirred at roomtemperature for 30 min. The solution was cooled at 0° C. and[1,3,2]dioxathiane 2,2-dioxide (3.6 g, 26.34 mmol) in THF (25 mL) wasadded. The resulting mixture was stirred at room temperature for 5hours, and the solvent was removed under vacuum. The residue wasdissolved in 6N HCl (15 mL) and heated at 100° C. for 16 hours. Themixture was cooled to room temperature, and the aqueous phase wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with H₂O (3×25 mL) and brine (25 mL), dried (MgSO4), filtered,and concentrated to produce 3-(biphenyl-4-yloxy)-propan-1-ol as a whitesolid (4.16 g, 63%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.57–7.49 (m, 4H),7.45–7.37 (m, 3H), 6.98 (dd, 2H, J=6.72, 2.14), 4.17 (t, 2H, J=5.9),3.88 (q, 2H, J=5.9), 2.07 (qn, 2H, J=5.9).

Step D

4-(3-Bromo-propoxy)-biphenyl

To a solution of 3-(biphenyl-4-yloxy)-propan-1-ol (1.00 g, 4.38 mmol) inCH₂Cl₂ (20 mL) at 0° C. was added triphenylphosphine (1.61 g, 6.14 mmol)and carbon tetrabromide (1.81 g, 5.47 mmol). The reaction mixture wasallowed to warm to room temperature, stirred for 1 hour, and extractedwith ethyl acetate (50 mL). The organic layer was washed with H₂O (3×50mL) and bine (3×25 mL), dried (MgSO4), filtered and concentrated. Thecrude product was purified by silica gel column chromatography (silicagel, hexanes/ethyl acetate, 9:1) to produce 4-(3-bromo-propoxy)-biphenyl(1.22 g, 95%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.57–7.29 (m, 7H), 6.98(dd, 2H, J=6.72, 1.88), 4.15 (t, 2H, J=5.92), 3.62 (t, 2H, J=6.44), 2.34(qn, 2H, J=5.92).

Step E

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid ethyl ester

To a solution of 3-(4-hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acidethyl ester (Example 132, Step A) (0.080 g, 0.31 mmol) in acetonitrile(10 mL) was added 4-(3-bromo-propoxy)biphenyl (Example 132, Step D)(0.101 g, 0.35 mmol) and potassium carbonate (0.115 g, 0.945 mmol). Theresulting suspension was stirred at 85° C. overnight. After cooling, thereaction mixture was diluted with ethyl acetate (10 mL), and water (10mL) was added. The organic layer was washed with water (10 mL) and brine(10 mL), dried (MgSO4), and concentrated. The crude product was purifiedby silica gel column chromatography (silica gel, hexanes/ethyl acetate,7:3) to produce3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid ethyl ester (0.086 g, 59%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.57–7.26(m, 7H), 6.98 (d, 2H, J=8.6), 6.87–6.73 (m, 3H), 4.25–4.17 (m, 6H), 3.91(dd, 1H, J=7.0, 5.6), 3.83 (s, 3H), 3.35 (s, 3H), 2.97–2.93 (m, 2H),2.31 (qn, 2H, J=5.9), 1.24 (t, 3H, J=7.3).

Step F

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid

The title compound was prepared from 3-{4-[3(biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionic acidethyl ester following the hydrolysis procedure described in Example 130,Step C. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.56–7.25 (m, 7H), 6.97 (d, 2H,J=8.9), 6.89–6.79 (m, 3H), 5.07 (b, 1H), 4.17 (q, 4H, J=5.6), 3.95 (dd,1H, J=7.5, 3.5), 3.82 (s, 3H), 3.32 (s, 3H), 3.11–2.86 (m, 2H), 2.28(qn, 2H, J=6.2).

Example 1332-Methoxy-3-{3-methoxy-{3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared following the procedure described forExample 132 (Steps A–E). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.32–7.24 (m,2H), 7.06–6.75 (m, 10H), 4.16 (q, 4H, J=6.2), 3.97 (dd, 1H, J=7.8, 4.3),3.82 (s, 3H), 3.37 (s, 3H), 3.08 (dd, 1H, J=14.2, 4.0), 2.94 (dd, 1H,J=14.5, 7.8); 2.27 (qn, 2H, J=6.2).

Example 134(2S)-3-(4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-(3-Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester

To a solution of 3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethylester (0.113 g, 0.5 mmol) in CH₃CN (3 mL) cooled to 0° C.,N-chlorosuccinimide (0.067 g, 0.5 mmol,) was added in various portions.The mixture was allowed to warm to room temperature and was stirred for8 hours. The mixture-was concentrated under vacuum, and the resultingoil was washed with CCl₄ (4 mL). The precipitate which formed wasfiltered, and the filtrate was concentrated to give a mixture of3-(3-chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester and3-(3,5-Dichloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl esteras a brown oil which was purified by ultraviolet-directed HPLC. Acolorless oil was obtained (0.020 g, 14%). ¹H-NMR (200.15 MHz, CDCl₃): δ7.18 (d, 1H, J=2.15), 7.02 (dd, 1H, J=8.32, 2.15), 6.91 (d, 1H, J=8.32),4.18 (q, 2H, J=7.25), 3.88 (dd, 1H, J=7.24, 5.62), 3.35 (s, 3H), 2.92(dd, 2H, J=6.31, 2.42), 1.24 (t, 3H, J=7.2).

Step B

(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionicacid ethyl ester

3-(3 Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester(0.020 g, 0.077 mmol) was dissolved in CH₃CN (3 mL) and4-(3-bromo-propoxy)-biphenyl (Example 132, Step D), (0.025 g 0.085 mmol)and K₂CO₃ (0.032 g, 0.23 mmol) were added. The mixture was heated to 85°C. and stirred for 5 hours. After cooling, water (2 mL) was added. Themixture was extracted in EtOAc (3×10 mL), washed with H₂O (2×5 mL) andbrine (2×5 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (silica gel, hexanes/ethyl acetate 9:1) to produce3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionicacid ethyl ester (0.017 mg, 48%). ¹H-NMR (200.15 MHz, CDCl₃): δ7.57–7.24 (m, 9H), 7.02–6.89 (m, 3H), 4.28–4.12 (m, 5H), 3.89 (dd, 1H,J=7.24, 5.62), 3.62 (t, 1H, J=6.44), 3.36 (s, 3H), 2.93 (dd, 2H, J=6.31,2.42), 2.32 (qn, 2H, J=5.10), 1.25 (t, 3H, J=7.2).

Step C

(2S)3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionicacid

The title compound was prepared as follows:3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionicacid ethyl ester (0.017 g, 0.037 mmol) was dissolved in 0.25 M ethanolicNaOH solution (0.3 mL, 0.075 mmol). The mixture was stirred 16 hours atroom temperature and water was added. The aqueous layer was extractedwith Et₂O (3×5 mL). The aqueous layer was acidified to pH=1 with 1 N HCland extracted with Et₂O (5×10 mL). The organic layer was dried (MgSO₄)and concentrated under vacuum to give the title compound as a yellow oil(0.006 mg, 38%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.57–7.25 (m, 9H),7.0–6.86 (m, 3H), 4.23 (q, 4H, J=6.18), 3.96 (dd, 1H, J=7.24, 4.28),3.40 (s, 3H), 3.06 (dd, 1H, J=14.5, 4.28), 2.92 (dd, 1H, J=14.5, 7.24),2.32 (qn, 2H, J=5.92).

Example 1353-{3-Chloro-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared as a same manner in Example 134, butusing 4-(3-bromopropoxy)-1-phenoxybenzene as material for the couplingreaction

Example 136′3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionicacid

The title compound was prepared as a same manner in Example 134, butusing [4-(3-Bromo-propoxy)-phenyl]-phenyl-methanoneas material for thecoupling reaction

Example 1373-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3,5-dichloro-phenyl}-2-methoxy-propionicacid

Step A3-(3,5-Dichloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester

To a solution of 3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethylester (0.113 g, 0.5 mmol) in CH₃CN (3 mL) cooled to 0° C.,N-chlorosuccinimide (0.067 g, 0.5 mmol,) was added in various portions.The mixture was allowed to warm to room temperature and was stirred for8 hours. The mixture was concentrated under vacuum, and the resultingoil was washed with CCl₄ (4 mL). The precipitate which formed wasfiltered and the filtrate was concentrated to give a mixture of3-(3-chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester and3-(3,5-Dichloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl esteras a brown oil which was purified by ultraviolet-directed HPLC.

Step B

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3,5-dichloro-phenyl}-2-methoxy-propionicacid

The title compound was prepared staring from compound from Step A andusing the same procedure as in 0.

Example 1383-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-propionicacid

Step A2-(3-Fluoro-4-methoxy-phenyl)-[1,3]-dioxolane

A solution of 3-fluoro-4-methoxy-benzaldehyde (463 mg, 3 mmol), ethyleneglycol (0.86 mL, 15 mmol) and PPTs (75 mg, 0.3 mmol) in toluene (15 mL)was heated at reflux with aceotropic removal of water for 6 hours. Thesolvent was evaporated and the residue was diluted with methylenechloride (20 mL), washed with water (2×10 mL) and dried (MgSO₄).Concentration produced 2-(3-Fluoro-4-methoxy-phenyl)-[1,3]-dioxolane asa colorless oil (550 mg, 92%). ¹H-NMR (CDCl3, 200.15 MHz): δ 7.24–7.15(m, 2H), 6.92 (t, 1H, J=8.5), 5.71 (s, 1H), 4.10–3.98 (m, 4H), 3.86 (s,3H).

Step B

4-[1,3]Dioxolan-2-yl-2-fluorophenol

A solution of 2-(3-Fluoro-4-methoxy-phenyl)-[1,3]-dioxolane (250 mg,1.26 mmol) and Sodium thiomethoxide (106 mg, 1.51 mmol) in dryN,N-dimethylformamide (3.5 mL) was heated at 100° C. under nitrogen for4 hours. Then a saturated solution of ammonium chloride (15 mL) wasadded and the aqueous layer extracted with methylene chloride (4×10 mL).The combined organic layers were dried (Na₂SO₄), filtered andconcentrated under vacuum. The residue was chromatographed (silica gel,hexanes/ethyl acetate 7:3) to produce4-[1,3]dioxolan-2-yl-2-fluoro-phenol as a pale brown oil (120 mg, 52%).¹H-NMR (CDCl3, 200.15 MHz): δ 7.24–7.01 (m, 2H), 6.88 (t, 1H, J=8.4),6.07 (s_(a), 1H), 5.71 (s, 1H), 4.13–3.95 (m, 4H).

Step C

3-Fluoro-4-hydroxy-benzaldehyde

A solution of 1N HCl (1 mL) and 4-[1,3]dioxolan-2-yl-2-fluoro-phenol(250 mg, 1.35 mmol) in THF (2 mL) was stirred, at room temperature for 1hour. The mixture was diluted with water and extracted with methylenechloride (4×10 mL). The combined organic layers were dried (Na₂SO₄),filtered and concentrated under vacuum. The residue was chromatographed(silica gel, hexanes/ethyl acetate 1:1) to produce3-Fluoro-4-hydroxy-benzaldehyde as a white solid (180 mg, 95%). ¹H-NMR(CDCl3, 200.15 MHz): 9.84 (d, 1H, J=2.4), 7.68–7.59 (m, 2H), 7.15 (t,1H, J=8.5), 6.5 (s_(a), 1H).

Step D

4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-benzaldehyde

Potassium tert-butoxide (198 mg, 1.76 mmol) was added, at 0° C., to asolution of 3-Fluoro-4-hydroxy-benzaldehyde (235 mg, 1.68 mmol) in dryN,N-dimethylformamide (2 mL). The mixture was stirred for 10 minutes.4-(3-Bromo-propoxy)-biphenyl (example 23, Step D) (539 mg, 1.84 mmol)was added and the reaction was stirred for 24 hours at room temperature.The mixture was diluted with water (15 mL) and extracted with ethylacetate (4×15 mL). The combined organic layers were dried (Na₂SO₄),filtered, and concentrated under vacuum to produce a solid which waswashed with hexanes to produce4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-benzaldehyde as a pale brownsolid (490 mg, 83%). ¹H-NMR (CDCl3, 200.15 MHz): δ 9.83 (d, 1H, J=2.2),7.64–7.23 (m, 9H), 7.09 (t, 1H, J=8.2), 6.96 (d, 2H, J=8.8), 4.32 (t,2H, J=5.9), 4.21 (t, 2H, J=5.9), 2.35 (qn, 2H, J=5.9).

Step E

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-3-hidroxy-2-methoxy-propionicacid methyl ester

To a solution of sodium bis(trimethylsilyl)amide 1N (0.71 mL, 0.71 mmol)in dry THF (5 mL), was added dropwise methyl methoxyacetate (57 μL, 0.57mmol) at −78° C. The solution was stirred for 1 hour.4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-benzaldehyde (220 mg, 0.626mmol) was added and the mixture warmed to 0° C. and stirred for 3additional hours. The mixture was quenched with 1N HCl (2 mL), dilutedwith water (20 mL) and extracted with dichloromethane (4×15 mL). Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedunder vacuum. The residue was chromatographed (silica gel, hexanes/ethylacetate 7:3) to produce3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-3-hidroxy-2-methoxy-propionicacid methyl ester as a colourless oil (62 mg, 24%). ¹H-NMR (CDCl3,200.15 MHz): δ 7.55–7.25 (m, 8H), 7.15–6.89 (m, 5H), 4.91–4.79 (m, 1H),4.24–4.18 (m, 4H), 3.92 and 3.81 (2d, 1H, J=5.86 and 5.48), 3.67 and3.64 (2s, 3H), 3.40 and 3.36 (2s, 3H), 3.01 and 2.94 (2d, 1H, 5.12 and5.12), 2.29 (qn, 2H, J=5.9).

Step F

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-propionicacid methyl ester

Trifluoroacetic anhydride (0.056 mL, 0.395 mmol) and pyridine (0.048 mL,18.9 mmol) were added to a solution of3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-3-hidroxy-2-methoxy-propionicacid methyl ester (90 mg, 0.197 mmol) in methylene chloride (2; mL) at0° C. The mix was stirred for 4 hours at room temperature and quenchedwith 1N HCl (10 mL). The layers were separated and the aqueous extractedwith methylene chloride (3×20 mL). The combined organic layers wereevaporated and the residue dissolved in ethyl acetate (50 mL). 10%palladium on carbon (90 mg) was added to the solution and mixture wasstirred under hydrogen pressure (5 atm) for 16 hours, filtered through apad of celite and concentrated under vacuum. The residue waschromatographed (silica gel, hexanes/ethyl acetate 4:1) to produce3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-propionicacid methyl ester as a colorless oil (40 mg, 46%). ¹H-NMR (CDCl3, 200.15MHz): δ 7.58–7.49 (m, 4H), 7.46–7.37 (m, 2H), 7.34–7.24 (m, 1H),7.01–6.90 (m, 5H), 4.22 (t, 4H, J=5.9), 3.93 (dd, 1H, J=7.3, 5.3), 3.73(s, 3H), 3.37 (s, 3H), 2.97–2.92 (m, 2H), 2.31 (qn, 2H, J=5.9).

Step G

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-fluoro-phenyl}-2-methoxy-propionicacid methyl ester following the Standard Procedure E: white solid (38mg, 98%). ¹H-NMR (CDCl3, 200.15 MHz): δ 7.58–7.49 (m, 4H), 7.46–7.37 (m,2H), 7.34–7.24 (m,1H), 7.01–6.90 (m, 5H), 4.23 (t, 2H, J=5.9), 4.22 (t,2H, J=5.9), 3.97 (dd, 1H, J=7.4, 4.4), 3.4 (s, 3H), 3.12–2.89 (m, 2H),2.31 (qn, 2H, J=5.9).

Example 1393-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2-methoxy-propionicacid

Step A3-Bromo-4-hydroxy-benzaldehyde

A solution of bromine (0.88 mL, 17.18 mmol) in chloroform (20 mL) wasadded dropwise at room temperature to a solution of4-hydroxybenzaldehyde (2 g, 16.36 mmol) in chloroform (40 mL) and themixture was stirred for 0.5 hour at room temperature and 1 more hour at40° C. A saturated solution of NaHCO₃ (30 mL) was added and the organiclayer separated. The aqueous layer was extracted with methylene chloride(3×20 mL). Thee combined organic layers were dried (Na₂SO₄), filteredand concentrated under vacuum. The residue was chromatographed (silicagel, methylene chloride-methanol 98:2) to affored3-Bromo-4-hydroxy-benzaldehyde as a white solid (1.1 g, 34%). ¹H-NMR(CDCl₃, 200.15 MHz): 9.80 (s, 1H), 8.02 (d, 1H, J=1.8), 7.75 (dd, 1H,J=8.4, 1.8), 7.12 (d, 1H, J=8.4), 6.19 (s, 1H).

Step B

4-Benzyloxy-3-bromo-benzaldehyde

3-Bromo-4-hydroxy-benzaldehyde (1.9 g, 9.45 mmol) was added slowly, at0° C., to a suspension of NaH 95% (290 mg, 11.34 nol) in dryN,N-dimethylformamide (45 mL). The mixture was stirred for 0.5 hours.Benzyl chloride (1.3 mL, 11.34 mmol) was added and the reaction stirredat room temperature overnight. 1N HCl (40 mL) was added and the layersseparated. The aqueous layer was extracted with diethyl ether (5×50 mL)and the combined organic layers were dried (Na₂SO₄), filtered, andconcentrated under vacuum. The residue was chromatographed (silica gel,hexanes/ethyl acetate 9:1) to produce 4-Benzyloxy-3-bromo-benzaldehydeas a white solid (2.47 g, 90%). ¹H-NMR (CDCl3, 200.15 MHz): δ 9.82 (s,1H), 8.09 (d, 1H, J=1.8), 7.76 (dd, 1H, J=8.4, 1.8), 7.47–7.32 (m, 5H),7.02 (d, 1H, J=8.4), 5.24 (s, 2H.

Step C

4-Benzyloxy-3-trifluoromethyl-benzaldehyde

Methyl 2,2-difluoro-2-(fluorosulfonyl)-acetate (1.25 mL, 9.78 mmol) wasadded to a suspension of dry CuI (745 mg, 3.91 mmol) and4-Benzyloxy-3-bromo-benzaldehyde (570 mg, 1.96 mmol) in dryN,N-dimethylformamide (10 mL). The mixture was stirred under nitrogen at120° C. for 6 hours in a sealed tube. The reaction mixture was cooled toroom temperature and diluted with water (20 mL). The aqueous layer wasextracted with diethyl ether (4×20 mL) and the combined organic layerswere dried (Na₂SO₄), filtered and concentrated under vacuum. The residuewas chromatographed (silica gel, hexanes/ethyl acetate 9:1) to produce4-Benzyloxy-3-trifluoromethyl-benzaldehyde as a white solid (120 mg,22%). ¹H-NMR (CDCl3, 200.15 MHz): δ 9.88 (s, 1H), 8.11 (d, 1H, J=1.8),7.98 (dd, 1H, J=8.6, 1.8), 7.44–7.31 (m, 5H), 7.14 (d, 1H, J=8.6), 5.27(s, 2H).

Step D

3-(4-hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-acrylic acid methylester

To a solution of sodium bis(trimethylsilyl)amide 1N (0.8 mL, 0.8 mmol)in THF (4 mL), was added dropwise methyl methoxyacetate (0.066 mL, 0.66mmol) at −78° C. After allowing the mixture to stir for 1 hour,4-Benzyloxy-3-trifluoromethyl-benzaldehyde (185 mL, 0.66 mmol) was addeddropwise. When the addition was finished the mixture was warmed to roomtemperature and stirred for 3 additional hours. Trifluoroaceticanhydride (0.28 mL, 1.98 mmol) was added and the mixture was stirred atroom temperature for 4 hours. The solvent was evaporated and the residuedissolved in ethyl acetate (50 mL). 10% palladium on carbon (200 mg) wasadded to the solution and the mixture stirred under hydrogen pressure (5atm) for 16 hours, filtered through a pad of celite and concentratedunder vacuum. The residue was chromatographed (silica gel, hexanes/ethylacetate 4:1) to produce 3-(4hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-acrylic acid methyl ester asa white solid (72 mg, 40%). ¹H-NMR ((CD₃)₂CO, 200.15 MHz): δ 9.65 (b,1H), 8.02 (d, 1H, J=1.8), 7.87 (dd, 1H, J=8.4, 1.8), 7.08 (d, 1H,J=8.4), 6.90 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H).

Step E

3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2-methoxy-acrylicacid methyl ester

Potassium tert-butoxide (15 mg, 0.13 mmol) was added at 0° C. to asolution of 3-(4-hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-acrylicacid methyl ester (35 mg, 0.126 mmol) in dry N,N-dimethylformamide (0.6mL). The mixture was stirred for 0.5 hours and4-(3-Bromo-propoxy)-biphenyl (example 23, Step D) (45 mg, 0.15 mmol) wasadded. The reaction was stirred for 6 hours at room temperature andquenched with a saturated solution of ammonium chloride (10 mL). Theaqueous layer was separated and extracted with methylene chloride (5×10mL). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated under vacuum. The residue was chromatographed (silica gel,hexanes/ethyl acetate 8:2) to produce3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-fluoromethyl-phenyl}-2-methoxy-acrylicacid methyl ester as a colorless oil (35 mg, 57%). ¹H-NMR (CDCl3, 200.15MHz): δ 8.00 (d, 1H, J=1.6), 7.89 (dd, 1H, J=8.6, 1.6), 7.46–7.26 (m,7H), 7.05–6.93 (m, 4H), 4.33–4.20 (m, 4H), 3.86 (s, 3H), 3.79 (s, 3H),2.33 (qn, 2H, J=5.9).

Step F

3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2-methoxy-acrylicacid

The title compound was prepared3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2-methoxy-acrylicacid methyl ester (35 mg, 0.072 mmol) following the Standard ProcedureE: white solid (31 mg, 92%). ¹H-NMR (CDCl3, 200.15 MHz): δ 8.02 (d, 1H,J=1.8), 7.88 (dd, 1H, J=8.6, 1.8), 7.57–7.28 (m, 7H), 7.08–6.96 (m, 4H),4.35–4.21 (m, 4H), 3.81 (s, 3H), 2.34 (qn, 2H, J=5.8).

Step G

3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethoxy-phenyl}-2-methoxy-propionicacid

The title compound was prepared as follows: A mixture of3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethyl-phenyl}-2-methoxy-acrylic(20 mg, 0.041 mmol) and magnesium (20 mg, 0.82 mmol) in methanol (1 mL)was stirred at room temperature for 80 hours. The reaction mixture wasquenched with 1N HCl (10 mL). The aqueous layer was extracted withmethylene chloride (5×10 mL). The combined organic layers were dried(MgSO₄), filtered and concentrated under vacuum to give3-{4-[3-(biphenyl-4-yloxy)-propoxy]-3-trifluoromethoxy-phenyl}-2-methoxy-propionicacid as a white solid (7 mg, 35%). ¹H-NMR (CDCl3, 200.15 MHz): δ7.57–7.32 (m, 9H), 7.00–6.95 (m, 3H), 4.27–4.19 (m, 4H), 3.97 (dd, 1H,J=7.3, 4.3), 3.41 (s, 3H), 3.16–2.93 (m, 2H), 2.31 (qn, 2H, J=5.8).

Example 140(2S)-3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4′-methoxy-biphenyl-3-yl}-2-methoxy-propionicacid

Step A(4-Hydroxy-3-iodide)-2-methoxy dihidroinnamic acid

(4-Hydroxy)-2-methoxy dihydrocinnamic acid (1 g, 4.4 mmol) was dissolvedin 30 mL of CH₃CN and cooled to −20° C. NIS was added (0.99 g, 4.43mmol) and the mixture was stirred for 8 hours. The solvent wasevaporated under vacuum and the crude oil was washed with CCl₄ withformation of a white solid. The solid was removed by filtration, and thefiltrate was concentrated and purified by column chromatography (silicagel, dichloromethane/MeOH 0.5%) Yellow oil (924 mg, 60%). ¹H-NMR (200.15MHz, CDCl₃): δ 7.49 (d, 1H, J=2), 7.04 (dd, 1H, J=2, 8.2), 6.80 (d, 1H,J=8.2), 6.03 (bs, 1H), 4.17 (q, 2H, J=7.2), 3.88 (dd, 1H, J=5.6, 7),3.33 (s, 3H), 2.88 (dd, 2H, J=2.4, 5.0), 1.21 (t, 3H, J=7.2)

Step B

(2S)-3-(6-Hydroxy-4′-methoxy-biphenyl-3-yl)-2-methoxy-propionic acid

A solution of (2S)(4-Hydroxy-3-iodide-)-2-methoxy dihidrocinnamic acid(197 mg, 0.56 mmol), 4-methoxyphenyl boronic acid (170.7 mg, 1.12 mmol)and tetrakis(triphenylphosphine)-palladium (0) (8.7 mg, 0.5 mmol) in 11mL of a mixture 20:1 toluene/ethanol together with 2 mL of a 2N Na₂CO₃was heated to 120° for 16 hours under nitrogen atmosphere. The reactionmixture was cooled to room temperature and dilute with ethyl acetate (20mL). It was washed with H₂O (3×5 mL) and brine (3×5 mL). The combinedorganic layers were dried (MgSO₄), filtered and concentrated undervacuum. The resultant crude was purified by column chromatography(silica gel, hexanes/ethyl acetate 8:2). Colorless oil (123 mg, 67%).¹H-NMR (200.15 MHz, CDCl₃): δ 7.39 (dd, 2H, J=2.1, 6.4), 7.08–7.03 (m,2H), 6.97 (dd, 2H, J=2.1, 6.7), 6.85 (dd, 1H, J=1.3, 7.5), 5.60 (s, 1H),4.17 (q, 2H, J=7.0), 3.95 (dd, 1H, J=5.9, 6.4), 3.82 (s, 3H), 3.35 (s,3H), 2.97 (d, 2H, J=6.4), 1.22 (t, 3H, J=7.2)

Step C

(2S)-3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4′-methoxy-biphenyl-3-yl}-2-methoxy-propionicacid ethyl ester

3-{6-[3-(Biphenyl-4-yloxy)-propoxy]4′-methoxy-biphenyl-3-yl}-2-methoxy-propionicacid ethyl ester was prepared following the Standard Procedure B (THF).The residue was purified by chromatography (silica gel, hexanes/ethylacetate 8:2). White solid (13 mg, 17%). ¹H-NMR (200.15 MHz, CDCl₃): δ7.57 (m, 10H), 7.14 (dd, 2H, J=2.1, 7.8), 6.94–6.87 (m, 4H), 4.24–4.04(m, 6H), 3.94 (dd,1H, J=5.9, 6.9), 3.81 (s, 3H), 3.36 (s, 3H), 2.99 (d,2H, J=6.9), 2.18 (qn, 2H, J=5.9), 1.22 (t, 3H, J=7.2).

Step D

(2S)-3-{6-[3-(Biphenyl-4-yloxy)-propoxy]-4′-methoxy-biphenyl-3-yl}-2-methoxy-propionicacid

The title compound was prepared following the procedure described inexample 25 (Step C). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.57–6.87 (m, 16 H),4.15 (t, 2H, J=6.1), 4.07 (t, 2H, J=6.1), 4.01 (dd, 1H, J=7.2, 4.5),3.80 (s, 3H), 3.41 (s, 3H), 3.13 (dd, 1H, J=4.5, 14.4), 2.99 (dd, 1H,J=7.1, 14.4), 2.21 (qn, 2H, J=5.9).

Example 1413-{6-[3-{-(Biphenyl-4-yloxy)-propoxy]-4′-fluoro-biphenyl-3-yl}-2-methoxy-propionicacid

The title compound was prepared as in Example 140, with 4-fluorophenylboronic acid. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.57–6.87 (m, 16 H), 4.15(t, 2H, J=5.9), 4.04 (t, 2H, J=5.9), 4.02 (dd, 1H, J=7.2, 4.5), 3.41 (s,3H), 3.13 (dd, 1H, J=4.5, 14.2), 3.00 (dd, 1H, J=7.5, 14.2), 2.17 (qn,2H, J=5.9).

Example 1423-{6-[3-(Biphenyl-4-yloxy)-propoxy]-[1,1′;4′,1″]terphenyl-3-yl}-2-methoxy-propionicacid

The title compound was prepared as in Example 140, with 4-phenylphenylboronic acid

Example 1433-{6-[3-(Biphenyl-4-yloxy)-propoxy]-2′-methoxy-biphenyl-3-yl}-2-methoxy-propionicacid

The title compound was prepared as in Example 140, with 2-methoxyphenylboronic acid.

Example 1442-Methoxy-3-{6-[3-(4-phenoxy-phenoxy)-propoxy]-[1,1′:4′,1″]terphenyl-3-yl}-propionicacid

The title compound was prepared as in Example 140, with 4-diphenylboronic acid.

Example 1453-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-styryl-phenyl}-2-methoxy-propionicacid

The title compound was prepared as in Example 140, withtrans-2-phenylvinyl boronic acid

Example 1463-(4-{3-[4-(Hydroxy-phenyl-methyl)-phenoxy]-propoxy}-3-phenethyl-phenyl)-2-methoxy-propionicacid

A solution of3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-styryl-phenyl}-2-methoxy-propionicacid ethyl ester from Example 145, was dissolved in ethanol and treatedwith H₂ under balloon pressure. Filtered through a pad of celite andconcentrated to dryness. The compound thus obtained was treated understandard hydrolysis procedure C to give the title compound.

Example 1473-{4-[3-(4-Benzyl-phenoxy)-propoxy]-3-phenethyl-phenyl}-2-methoxy-propionicacid

The title compound was obtained as a secondary product of the reductionof3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-styryl-phenyl}-2-methoxy-propionicacid ethyl ester (from Example 145) as in Example 146, and washydrolyzed under the standard hydrolysis procedure C to afford theproduct.

Example 148(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-(3-Allyl-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester

To a solution of 3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethylester (1 eq) in acetone, K₂CO₃ (2 eq) and alkyl bromide (1.2 eq) wereadded and the mixture reaction was stirred at 55° C. over night.Quenched with water and extracted with ethyl acetate. The organic layerwas dried (MgSO₄) and concentrated to give3-(4-alkyloxy-phenyl)-2-methoxy-propionic acid ethyl ester. This crudeproduct was dissolved in Me₂NPh and heated to reflux for 6 hours andthen stirred at room temperature over 3 days. Refluxed again for 8 hoursand then poured into and ice-cold HCl 1M solution, extracted with ethylacetate and washed with water. Dried and concentrated to give a crudeproduct which was purified by chromatography to give the title product.

Step B

(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

(2S)-3-(3-Allyl-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl esterfrom Step A was allowed to react with4-(3-bromopropoxy)-1-phenoxybenzene under the Standard Procedure I togive the title compound.

Step C

(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester from Step B was hydrolyzed under the standardhydrolysis procedure C to afford the product.

Example 149(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-3-propyl-phenyl}-propionicacid

A solution of(2S)-3-{3-Allyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester, from Example 148, Step B, was dissolved in ethanol andtreated with H₂ under balloon pressure. Filtered through a pad of celiteand concentrated to dryness. The compound thus obtained was treatedunder, standard hydrolysis procedure C to give the title compound.

Example 1503-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acrylicacid

Step A4-Triisopropylsilanloxy-benzaldehyde

4-hydroxybenzaldehyde (3 g, 24.57 mmol), triisopropylsilyl chloride(5.52 mL, 25.79 mmol) and imidazol (2 g, 29.48 mmol) were dissolved in60 mL of DMF and the solution stirred at room temperature overnight.Water (120 mL) was added to the solution and the mixture extracted withdiethyl ether (3×50 mL). The combined extracts were washed with water(5×30 mL), saturated ammonium chloride (2×30 mL) and brine (20 mL) anddried (MgSO₄). Concentration produced an oil that was purified bychromatography (silica gel, hexanes/Ethyl acetate 20:1, R_(f)0.4) (75%).

¹H-NMR (CDCl₃, 200.15 MHz): 9.85 (s, 1H), 7.75 (d, 2H, J=8.9), 6.95 (d,2H, J=8.4), 1.31–1.20 (m, 3H), 1.10 (s, 18H).

Step B

2-Methyl-4-triisopropylsilanyloxy-benzaldehyde

To a solution of trimethylethylenediamine (0.45 mL, 3.48 mmol) in THF (9mL) at −20° C. was added Butyllithium 1.6M in hexanes (2.11 mL, 3.8mmol). The solution was stirred at −20° C. for 15 min. A solution of4-Triisopropylsilanyloxy-benzaldehyde (0.922 g, 3.31 mmol) was addeddropwise and the solution stirred for 15 min at −20° C. Bu 16M inhexanes (6.21 ml, 9.93 mmol) was added dropwise and the solution kept inthe freezer at −20° C. for 26 hours. The solution was cooled to 40° C.and methyl iodide (3.71 mL, 59.60 mmol) was added. The solution wasallowed to reach room temperature and further stirred 30 ml. Thereaction was quenched with saturated ammonium chloride (20 mL) andextracted with ethyl acetate (3×30 mL). The combined extracts were dried(MgSO₄), concentrated under vacuum and purified by column chromatography(silica gel, hexanes/Ethyl acetate 20:1, R_(f)0.085) (49%). ¹H-NMR(CDCl₃, 200.15 MHz): δ 10.1 (s, 1H), 7.69 (d, 1H, J=8.3), 6.80 (dd,1H,J=8.6, 2.4), 6.72 (s, 1H), 0.61 (s, 3H), 1.33–1.19 (m, 3H), 1.12(s,18H).

Step C

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acrylicacid methyl ester

Methyl 2-methoxyacetate (0.450 mL, 4.53 mmol) was added to a solution ofNaHDMS (4.74 mmol) in 40 mL of THF cooled to −78° C. The mixture wasstirred at −78° C. for 30 min and then a solution of2-Methyl-4-trisopropylsilanyloxy-benzaldehyde (1.26 g, 4.3 mmol) in 20mL of THF was added dropwise. The solution was allowed to warm to 0° C.and stirred for 2.5 hours. The mixture was quenched with HCl 1N (50 mL)at 0° C., extracted with dichloromethane (3×40 mL), dried (MgSO₄) andconcentrated under vacuum. The residue was dissolved in dichloromethane(50 mL) and cooled to 0° C. To the solution was added trifluoroaceticanhidride (0.82 mL, 5.84 mmol), N,N-dimethylaminopyridine (0.025 g, 0.21mmol), and pyridine (0.379 mL, 4.59 mmol). And stirred at roomtemperature for 4 hours. The volatiles were eliminated under vacuum andthe residue dissolved in 100 mL of ethyl acetate. Palladium 10% onactivated carbon (0.9 g) was added and the mixture hydrogenated at roomtemperature (5 Atm H₂) for 14 hours. The solution was filtered through apad of celite and concentrated under vacuum. The residue was purified bycolumn chromatography (silica gel, hexanes/Ethyl acetate 3:1) thefractions with R_(f)0.08 were collected and concentrated under vacuum(0.249 g containing 3-(4-Hydroxy-2-methyl-phenyl)-2-methoxy-acrylic acidc.a. 85% pure by NMR). The residue was added to a solution of4-(3-Bromo-propoxy)-biphenyl (example 23, Step D) (0.359 g, 1.23 mmol),sodium iodide (0.05 g) and potassium tert-butoxide (126 mg, 1.12 mmol)in 5 mL of dimethylformamide. The solution was stirred at roomtemperature 24 hours, diluted with water and extracted with diethylether(3×30 mL). The combined organic layers were washed with water (5×30 ml),dried (MgSO₄) and concentrated under vacuum. The residue was purified bycolumn chromatography (silica gel, hexane:ethyl acetate 6:1, R_(f)0.22).(0.18 mg, 10%). ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.98 (d, 1H, J=8.6),7.57–7.25 (m, 7H), 7.16 (s, 1H); 6.98 (dd, J=6.7, 2.1), 6.80–6.76 (m,2H), 4.20 (t, 4H, J=5.9), 3.85 (s, 3H), 3.69 (s, 3H), 2.36 (s, 3H), 2.29(t, 2H, J=6.2).

Step D

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acrylicacid

The title compound was prepared from3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acrylicacid methyl ester following the general procedure B. ¹H-NMR (CDCl₃,200.15 MHz): 7.97 (d, 1H, J=8.4), 7.55–7.47 (m, 4H), 7.43–7.27 (m, 4H),6.96 (dd, 2H, J=6.6, 2.2), 6.79–6.75 (m, 2H), 4.19 (t, 4H, J=6.2), 3.69(s, 3H), 2.35 (s, 3H), 2.27 (t, 2H, J=6.2).

Example 1513-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-propionicacid

Step A3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-propionicacid methyl ester

Magnesium turnings (0.101 g, 4.17 mmol) was added to a solution of3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-acrylicacid methyl ester (Example 37, Step C) (0.09 g, 0.21 mmol) in methanol(2 mL) and diethyl ether (2 mL). The mixture was stirred at roomtemperature overnight and then quenched with HCl 3N until pH 7. Asaturated solution of ammonium chloride (10 mL) was added and themixture extracted with ethyl ether (3×10 mL). The combined extracts weredried (MgSO₄) and concentrated under vacuum. The residue was purified bycolumn chromatography. (Silica Gel, hexanes/Ethyl acetate 4.5:1,R_(f)0.31) (48%). ¹H-NMR (CDCl₃, 200.15 MHz): 7.57–7.29 (m, 7H), 7.07(d, 1H, J=8.1); 6.98 (dd, 2H, J=6.7, 2.1), 6.73 (s, 1H); 6.71 (d, 1H,J=11.8); 4.18 (dt, 4H, J=9.7, 6.2), 3.91 (dd, 1H, J=7.3, 6.2), 3.72 (s,3H), 3.32 (s, 3H), 2.97 (d, 2H, J=6.4), 2.31 (s, 3H); 2.27 (t, 2H,J=6.2).

Step B

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methyl-phenyl}-2-methoxy-propionicacid methyl ester following the general procedure B. (71%). ¹H-NMR(CDCl₃, 200.15 MHz): δ 7.55–7.27 (m, 7H); 7.09 (d, 1H, J=8.1); 6.96 (d,2H, J=9.2); 6.71–6.67 (m, 2H); 4.15 (dt, 4H, J=9.1, 6.2); 3.92 (dd, 1H,J=8.4, 4.4); 3.31 (s, 3H); 3.08 (dd, 1H, J=14.6, 4.4); 2.93 (dd, 1H,J=14.3, 8.4); 2.30 (s, 3H); 2.25 (qn, 2H, J=6.2).

Example 1523-{3-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid

Step A3-(3-Benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester

To a solution of NaHMDS (1.1 eq) in dry THF at −78° C. a mixture of3-benzyloxy-benzaldehyde (1 eq) and methoxy-acetic acid methyl ester(1.25 eq) in THF were added dropwise and the mixture reaction at thistemperature over 1.5 hours. Then the reaction was quenched with HCl 3Nand allowed to rise room temperature. Washed with brine and extractedwith ether. The organic layer was dried and concentrated to dryness to,give after chromatography in silica gel the title product.

Step B

3-(3-Benzyloxy-phenyl)-2-methoxy-acrylic acid methyl ester

A mixture of 3-(3-Benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acidmethyl ester (1 eq), mesylchloride (1 eq) triethylamine (4 eq) and acatalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at roomtemperature overnight. The Reaction mixture was diluted with ether andwashed with HCl 1N. Dried and concentrated in vacuo to give a residuewhich was chromatographed in silica gel to yield the title compound.

Step C

3-(3-Benzyloxy-phenyl)-2-methoxy-propionic acid methyl ester

Compound from Step B was dissolved in methanol and treated withmagnesium. The flask was placed in an ice bath for 5 min and then thereaction mixture was stirred at room temperature for 4 hours. Washedwith HCl 3N and extracted with ether. Dry and concentrated to dryness toget the title compound.

Step D

3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester

A solution of 3-(3-Benzyloxy-phenyl)-2-methoxy-propionic acid methylester in methanol was treated with a catalytic amount of C—Pd (0.1 eq)and then H₂ was bubbled through the mixture and stirred overnight. Themixture reaction was concentrated and reconstituted in ethyl acetate,filtered through a pad of celite and concentrated in vacuo to give thetitle compound.

Step E

3-{3-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid

A mixture of 3-(3-Hydroxyphenyl)-2-methoxy-propionic acid methyl ester(1 eq) from Step D, Cesium Carbonate (3 eq) and4-(3-bromopropoxy)biphenyl (1 eq) in DMF and in a 10 mL tube was shakedin an orbital agitator over a weekend. The mixture was filtered througha hydrofobic syringer and evaporated in a speed-vac apparatus. Thendiluted with NaOH 1N-Ethanol and stirred overnight. Then HCl 3N wasadded and the reaction mixture was concentrated to remove the ethanol invacuo, reconstituted in dichloromethane and filtered through ahydrofobic syringe. The organic layer was evaporated to give the titlecompound. MS (ES) for C₂₅H₂₆O₅ [M+NH⁴]⁺: 424.2, [M+Na]⁺: 429.2. ¹H-NMR(CDCl₃, 200.15 MHz): 7.57–7.17 (m, 9H), 6.98 (dd, 2H, J=6.7, 1.9),6.84–6.81 (m, 3H), 4.19 (dd, 4H, J=14.0, 6.4), 4.03 (dd, 1H, J=7.3,4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0,7.5), 2.28 (qui, 2H, J=5.9)ppm.

Example 153′2-Methoxy-3-{3-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid

The title compound was prepared from3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester from Example152, Step D with 4-(3-bromopropoxy)1-phenoxybenzene in a manneranalogous as in Example 152, Step E. MS (ES) for C₂₅H₂₆O₆ [M+NH₄]⁺:440.2, [M+Na]⁺: 445.2. ¹H-NMR (CDCl₃, 200.15 MHz): 7.33–7.17 (m, 3H),7.07–6.78 (m, 10H), 4.15 (dt, 4H, J=1.9, 6.2), 4.03 (dd, 1H, J=7.3,4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0,7.5), 2.25 (qui, 2H, J=5.9)ppm.

Example 1543-{3-[3-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester from Example152, Step D with [4-(3-Bromo-propoxy)-phenyl]-phenyl-methanone in amanner analogous as in Example 152, Step E. MS (ES) for C₂₆H₂₆O₆ M+H]⁺:435.2, [M+Na]⁺: 457.2. 1H-NMR (CDCl3, 200.15 MHz): 7.83–7.72 (m, 4H),7.56–7.42 (m, 3H), 7.21 (dd, 2H, J=9.1, 7.0), 6.97 (d, 2H, J=8.9), 6.82(d, 1H, J=14.2), 6.82 (s, 2H), 4.25 (t, 2H, J=6.2), 4.16 (t, 2H, J=5.9),4.02 (dd, 1H, J=7.5, 4.3), 3.40 (s, 3H), 3.12 (dd, 1H, J=14.0, 4.3),2.98 (dd, 1H, J=14.2, 7.5), 2.29 (qui, 2H, J=5.9).

Example 1552-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionicacid

Step A2-Methoxy-3-(3-trifluoromethanesulfonyloxy-phenyl)-propionic acid methylester

The title compound was prepared using the same procedure as in Example1, Step A starting from 3-(3-Hydroxy-phenyl)-2-methoxy-propionic acidmethyl ester.

Step B

3-[3-(5-Hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid methylester

The title compound was prepared from 4-butyn-1-ol following theprocedure described, in Example 1, Step B.

Step C

3-[3-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid methyl ester

To a solution of3-[3-(5-Hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid methylester, and CBr₄ dissolved in dichloromethane at 0° C.,triphenylphosphine was added and the mixture reaction was stirred atroom temperature over 5 hours.

The reaction then was diluted with water and extracted with ether.

Chromatographied to give the title compound.

Step D

2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl-3-phenyl]-propionicacid methyl ester

A mixture of 3-[3-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acidmethyl ester (1 eq), 4-phenoxyphenol (1 eq) and Cesium carbonate (3 eq),in DMF was stirred overnight. Then diluted in water and extracted withether to give after dry in vacuo the title compound.

Step E

2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionicacid

The title compound was prepared following the Standard HydrolysisProcedure C and starting from2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionicacid methyl ester from Step D. MS (ES) for C₂₇H₂₆O₅ [M+NH⁴]⁺: 448.2,[M+Na]⁺: 453.2. ¹H-NMR (CDCl₃, 200.15 MHz): 7.33–7.17 (m, 7H), 7.07–6.88(m, 7H), 4.11 (t, 2H, J=0.2), 4.00 (dd, 1H, J=7.5, 4.0), 3.39 (s, 3H),3.11 (dd, 1H, J=14.0, 4.3), 2.96 (dd, 1H, J=14.5, 7.8), 2.63 (t, 2H,J=7.0), 2.08 (qui, 2H, J=6.7).

Example 1562-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pentyl]-phenyl}-propionic acid

The title compound was prepared from2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionicacid of Example 155, Step E, and treated with Pd—C (0.1 eq) in ethylacetate and H₂. Filtered through celite and concentrated to give thecompound. MS (ES) for C₂₇H₃₀O₅ [M+H]⁺: 435.2, [M+NH₄]⁺: 452.2. ¹H-NMR(CDCl₃, 200.15 MHz): 7.34–7.19 (m, 3H), 7.09–6.84 (m, 10H), 4.02 (dd,1H, J=7.5, 4.6), 3.94 (t, 2H, J=6.5), 3.39 (s, 3H), 3.13 (dd, 1H,J=14.0, 4.3), 3.00 (dd, 1H, J=14.0, 7.5), 2.63 (t, 2H, J=7.8), 1.88–1.45(m, 6H)ppm.

Example 1572-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pentanoyl]-phenyl}-propionic acid

The title compound was prepared from2-Methoxy-3-{3-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionicacid methyl ester (Example 155, Step D) and following the same procedureas in Example 57, and a standard hydrolysis procedure C to get thecompound.

Example 1583-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A2-Allyl-4-phenoxy-phenol

To a solution of 4-phenylphenol (1 eq) in acetone, K₂CO₃ (2 eq) andalkyl bromide (1.2 eq) were added and the mixture reaction was stirredat 55° C. overnight. Quenched with water and extracted with ethylacetate. The organic layer was dried (MgSO₄) and concentrated to give4-allyloxybiphenyl. This crude product was dissolved in Me₂NPh andheated to reflux for 6 hours and then stirred at room temperature over 3days. Refluxed again for 8 hours and then poured into and ice-cold HCl1M solution, extracted with ethyl acetate and washed with water. Driedand concentrated to give a crude product which was purified bychromatography to give the title product.

Step B

3-(3-Allyl-biphenyl-4-yloxy)-propan-1-ol

The product obtained in Step A (1.1 eq) was dissolved in THF and treatedwith t-BuOK (1.15 eq) and allowed to react for 2 hours. Then a solutionof [1,3,2]Dioxathiolane 2,2-dioxide (1.0 eq) was added and the mixturereaction was stirred overnight quenched with HCl 6N and refluxed thereaction overnight. Extracted with ethyl acetate, washed with brine andconcentrated to give the title compound.

Step C

3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

A solution of compound from Step B in dichloromethane was treated withCBr₄ (1.12 eq) and PPh₃ (1.4 eq) and allow to react for 1.5 hours. Theproduct isolated after chromatography of this reaction was treated underStandard Procedure I with (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionicacid ethyl ester to give the title compound.

Step D

3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared by using the standard HydrolysisProcedure (NaOH) C.

Example 159(2S)-2-Methoxy-3-{4-[3-(3-propyl-biphenyl-4-yloxy)-propoxy]-phenyl}-propionicacid

3-{4-[3-(3-Allyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid from Example 158, Step D dissolved in ethyl acetate was treatedwith Pd(C) 10% under balloon pressure for 6 hours. Filtered throughcelite and concentrated to dryness to give the title compound.

Example 160(2S)-3-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A2-Allyl-4-phenoxyphenol

The title compound was prepared in a same manner as in Example 158, StepA, starting from 4-phenoxyphenol.

Step B

2-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-3-methoxy-propionicacid ethyl ester

3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester and2-Allyl-4-phenoxy-phenol from Step A were allowed to react underStandard Procedure I to give the title compound.

Step C

(2S)-3-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared by using the standard HydrolysisProcedure C (NaOH) to yield the compound.

Example 161(2S)-2-Methoxy-3-{4-[3-(4-phenoxy-2-propyl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from2-{4-[3-(2-Allyl-4-phenoxy-phenoxy)-propoxy]-phenyl}-3-methoxy-propionicacid ethyl ester from Example 160, Step B which was treated in ethylacetate with Pd(C) and H₂ in balloon presure to give after filtrationthe corresponding reduced product which was hydrolyzed under StandardProcedure C to give the title compound.

Example 1623-{4-[3-Biphenyl-4-yloxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propionicacid

Step A4-Benzyloxy-3-methyl-benzaldehyde

A mixture of benzyl bromide and 4-hydroxy-3-methylbenzaldehyde weretreated under Standard Procedure I to give the title product.

Step B

3-(4-Benzyloxy-3-methyl-phenyl)-3-hydroxy-2-methoxy-propionic acid ethylester

To a solution of NaHMDS (1.1 eq) in dry THF at −78° C. a mixture of4-Benzyloxy-3-methyl-benzaldehyde (1 eq) and Methoxy-acetic acid methylester (1.25 eq) in THF were added dropwise and the mixture reaction atthis temperature over 1.5 hours. Then the reaction was quenched with HCl3N and allowed to rise room temperature. Washed with brine and extractedwith ether. The organic layer was dried and concentrated to dryness togive after chromatography in silica gel the title product.

Step C

3-(4-Benzyloxy-3-methyl-phenyl-2-methoxy-acrylic acid ethyl ester

A mixture of3-(4-Benzyloxy-3-methyl-phenyl)-3-hydroxy-2-methoxy-propionic acid ethylester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq) and a catalyticamount of DMAP (0.1 eq) in dichloromethane was stirred at roomtemperature over night. The reaction mixture was diluted with ether andwashed with HCl 1N. Dried and concentrated in vacuo to give a residuewhich was chromatographed in silica gel to yield the title compound.

Step D

3-(4-Benzyloxy-3-methyl-phenol)-2-methoxy-propionic acid ethyl ester

Compound from Step C was dissolved in methanol and treated withmagnesium.

The flask was placed in an ice bath for 5 min and then the reactionmixture was stirred at room temperature for 4 hours. Washed with HCl 3Nand extracted with ether. Dry and concentrated to dryness to get thetitle compound.

Step E

3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl ester

A solution of 3-(4-Benzyloxy-3-methyl-phenyl)-2-methoxy-propionic acidethyl ester in ethyl acetate was treated with a catalytic amount of C—Pd(0.1 eq) and then H₂ was bubbled through the mixture and stirred 2hours. The mixture reaction was filtered through a pad of celite andconcentrated in vacuo to give the title compound.

Step F

(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propionicacid ethyl ester

A mixture of 3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acidethyl ester and from Step E and 4-(3-bromopropoxy)biphenyl were treatedunder standard condition I to give the title product.

Step G

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propionicacid

The title compound was prepared from compound from Step F under Standardhydrolysis procedure C using NaOH.

Example 1632-Methoxy-3-{3-methyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid

Step A2-Methoxy-3-{3-methyl-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid ethyl ester

A mixture of 3-(Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acid ethylester and from Example 162, Step E and 4-(3-bromopropoxy)-phenoxyphenylwere treated under standard condition I to give the title product.

Step B

The title compound was prepared from compound from Step A under Standardhydrolysis procedure C using NaOH.

Example 1643-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propionicacid

Step A3-[4-(3-Benzoyl-phenoxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propionicacid ethyl ester

A mixture of 3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acidethyl ester and from Example 162, Step E and[4-(3-Bromo-propoxy)-phenyl]-phenyl-methanone were treated understandard condition I to give the title product.

Step B

3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methyl-phenyl}-2-methoxy-propionicacid

The title compound was prepared from compound from Step A under Standardhydrolysis procedure C using NaOH.

Example 165(2S)-3-{4-[3-(Dibenzofuran-2-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A3-(Dibenzofuran-2-yloxy-propan-1-ol

A solution of 2-hydroxydibenzofurane, potassium tert-butoxide and[1,2,3]dioxathiane-2,2-dioxide were treated as the same manner as inExample 132, Step C, to give the title product.

Step B

2-(3-Bromo-propoxy)-dibenzofuran

Starting from compound of Step A and following the procedure describedin Example 132, Step D we obtained the title compound.

Step C

3-{4-[3-(Dibenzofuran-2-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acidethyl ester

A mixture of 2-(3-Bromo-propoxy)-dibenzofuran and(2S)-3-(4-hydroxy-phenyl)-2-methoxy propionic acid ethyl ester wereallowed to react under the Standard Procedure I to give the titlecompound.

Step D

(2S)-3-{4-[3-(Dibenzofuran-2-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from Step C using the standardhydrolysis procedure C (NaOH).

Example 166(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxyimino-methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid (Example 95), and was treated under the same conditions as inExample 61, to give the title compound.

Example 167(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxy-methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionicacid

Step A(2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxy-methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionicacid ethyl ester

The title compound was prepared from(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester (Example 95) which was dissolved in methanol andtreated at 0° C. with NaBH₄ (2 eq) for 6 hours. Washed with water andextracted with dichloromethane to give after purification bychromatography the title compound.

Step B

2S)-3-[4-(3-{4-[(4-Fluoro-phenyl)-hydroxy-methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionicacid

The title compound was prepared from Step A by standard hydrolysisprocedure C (NaOH).

Example 168(2S)-2-Methoxy-3-(4-{3-[4-(4-piperidin-1-benzoyl]-propoxy}-phenyl)-propionicacid

Step A(2S)-2-Methoxy-3-(4-{3-[4-(4-piperidin-1-yl-benzoyl)-phenoxy]-propoxy}-phenyl)-propionicacid ethyl ester

To a solution of(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester (Example 95) in DMSO, piperydine (3 eq) was added andthe mixture reaction was heated to 140° C. for 2 days. The reaction wasextracted with ethyl acetate and washed (several times) with water.Concentrated to dryness and chromatographied to give the title compound.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(4-piperidin-1-yl-benzoyl)-phenoxy]-propoxy}-phenyl)-propionicacid

The title compound was prepared from Step A by standard hydrolysisprocedure C (LiOH). MS (ES) for C₃₁H₃₅NO₆ [M+H]⁺: 518.

Example 169(2S)-2-Methoxy-3-(4-{3-[4-(4-morpholin-4-yl-benzoyl)-phenoxy]-propoxy}-phenyl)-propionicacid

Step A(2S)-2-Methoxy-3-(4-{3-[4-(4-morpholin-4-yl-benzoyl)-phenoxy-propoxy}-phenyl)-propionicacid ethyl ester

To a solution of(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester (Example 95) in DMSO, morpholyne (3 eq) was added andthe mixture reaction was heated to 140° C. for 2 days. The reaction wasextracted with ethyl acetate and washed (several times) with water.Concentrated to dryness and chromatographed to give the title compound.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(4-morpholin-4-benzoyl)-phenoxy]-propoxy}-phenyl)-propionicacid

The title compound was prepared from Step A by standard hydrolysisprocedure C (LiOH). MS (ES) for C₃₀H₃₃NO₇ [M+H]⁺: 520.

Example 170(2S)-3-(4-{3-[4-(4-Hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

A solution of(2S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid (85 mg) (Example 95) and KOH (100 mg) in chlorobenzene (0.3 ml)with water (1 ml) were heated in sealed tube at 200° C. for 3 days.Extracted with ethyl acetate, dried and concentrated to dryness to givea crude product which was purified by chromatography to give the titlecompound. MS (ES) for C₂₆H₂₆O₇ [M+H]⁺: 451.

Example 1712S-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoic acidsodium salt

Step 1: 1-chloro-3-(4-phenoxyphenyl propane (a)

The compound of 4-phenoxyphenol (81.03 g, 435.5 mmol) was dissolved in810 ml MEK at ambient temperature under Nitrogen. Powdered potassiumcarbonate (577.16 g, 4,176.27 mmol) was added followed by1,3-dichloropropane (300.00 g, 2,655.1 mmol), and the resulting solutionwas heated to reflux for 15.5 hours. The solution was cooled to roomtemperature, filtered and washed with 750 ml MEK. The filtrate wasconcentrated under vacuum to give a crude orange liquid. The crudeliquid was dissolved in 260 ml absolute MeOH at ambient temperature andstirred 5 minutes, which was then cooled in an ice/acetone/water bathfor 1.5 hours. White precipitate was filtered off and washed with 480 mlcold absolute MeOH. The white solid was collected and dried under vacuumat 30° C. for 16 hours to afford about 81.87 g of compound (a).

Step 2:2S-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propanoic acidsodium salt

The compound (b) (10.9 g, 50 mmol) was dissolved in 50 ml absoluteethanol at ambient temperature. Sodium methoxide (4.05 g, 75 mmol) wasadded all at once, and the resulting solution was heated to reflux for30 minutes. The solution was cooled to 40° C. and the compound (a)(15.72 g, 75 mmol) was added all at once followed by 50 ml DMF and 50 mlDMSO. The clear red solution was heated to reflux for 30 minutes, andcooled to ambient temperature. The ethanol was removed under vacuum at60° C., and a mixture 100 ml of water and 100 ml MTBE was added. The toporganic layer was separated and discarded Fresh MTBE (100 ml) was addedand crystallization occurred. The biphasic slurry was stirred at ambienttemperature for 30 minutes, filtered and washed with 250 ml MTBE. Thewhite solid was dried under vacuum at 60° C. for 16 hours to affordabout 15.34 g of the title compound.

Example 172(2S)-3-[4-(3-{4-[Hydroxyamino-(4-hydroxy-phenyl)-methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-{3-[4-(4-Hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid (Example 170), and was treated under the same conditions as inExample 61, to give the title compound. MS (ES) for C₂₆H₂₇NO₇ [M−H]⁻:464.

Example 173(2S)-3-{4-[3-(4-Benzoyl-3-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester

The title compound was prepared from(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid ethylester from Example 171, Step B, and following the procedure described inExample 132, Step D we obtained the title compound.

Step B

3-{4-[3-(4-Benzoyl-3-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

A mixture of (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionicacid ethyl ester from Step A and 2,4-dihydroxybenzophenone were allowedto react under the Standard Procedure I to get to title compound.

Step C

(2S)-3-{4-[3-(4-Benzoyl-3-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from Step B by standard hydrolysisprocedure C (LiOH). MS (ES) for C₂₆H₂₆O₇ [M−H]⁻: 449.

Example 174(2S)-3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step A3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester

A mixture of (2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionicacid ethyl ester from 0, Step A and 2,4-dimethoxy-4′hydroxybenzophenonewere allowed to react under the Standard Procedure I to get to titlecompound.

Step B

(2S)-3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from Step A by standard hydrolysisprocedure C (LiOH). MS (ES) for C₂₈H₃₀O₈ [M−H]⁻: 493.

Example 1753-{4-[3-(4-Benzyl-phenoxy-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid

Step A3-[4-(3-Hydroxy-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid

A mixture of 3-(4-Hydroxy-3-methoxy-phenyl)-2-methoxy-propionic acidethyl ester (Example 130, Step A) and3-(tert-Butyl-dimethyl-silanyloxy)-propan-1-ol were treated underMitsounobu coupling standard conditions B using DIAD and toluene. Theproduct thus obtained was treated under Standard Procedure E forcleaveage protected alcohols to give the title product.

Step B

3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid

The title compound was prepared from3-[4-(3-Hydroxy-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid andfollowing the procedure described in Example 132, Step D we obtained thetitle compound.

Step C

3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid and4-benzylphenol following the Standard Procedure J. MS (ES) for C₂₇H₃₀O₆[M+NH₄]⁺: 468, [M+Na]⁺: 473.

Example 176 (S)-3-(4-benzyloxy-phenyl)-2-isopropoxy-propionic acid

Step 1: A solution containing(S)-5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one(S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g, 7.34 mmol),2,2-dimethoxypropane (18.63 g, 0.179 mol) and pyrididium p-toluenesulfonate (0.92 g, 3.66 mmol) in chloroform (80 mL) was heated to refluxfor 40 minutes under N₂. The reaction was cooled, diluted with water andextracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄) and thesolvent was removed in vacuo to give crude product which was purified bya flash chromatography using 10:1 hexanes:acetone to afford about 2.01 g(88%) of (S)-5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one. ¹HNMR (400 MHz, CDCl₃) δ 7.43–7.29 (m, 5H), 7.17 (d, 2H, J=8.80 Hz), 6.91(d, 2H, J=8.80 Hz), 5.04 (s, 2H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz),3.12 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 2.99 (dd, 1H, J=14.67 Hz, J=6.36Hz), 1.49 (s, 3H), 1.36 (s, 3H). MS (ES⁺) m/z exact mass calculated forC₁₉H₂₀O₄ (M+NH₄) 330. Found m/z 330.Step 2: (S)-3-(4-benzyloxy-phenyl)-2-isopropoxy-propionic acid A −78° C.solution of (S)-5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one(0.20 g, 0.64 mmol) and triethylsilane (0.223 g, 1.92 mmol) in CH₂Cl₂ (8mL) was treated dropwise with a 1 molar solution of TiCl₄ in CH₂Cl₂(0.64 mL, 0.64 mmol) under N₂. The solution was stirred at −78° C. for15 minutes and then quenched with water. The mixture was extracted withEtOAc, and the organic layer was dried (Na₂SO₂). The organic layer wasfiltered, and the solvent was removed in vacuo to give crude productwhich was purified by a flash chromatography using 5:1 hexanes:acetoneto afford 0.171 g (85%)(S)-3-(4-benzyloxy-phenyl)-2-isopropoxy-propionic acid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.50 (bs, 1H), 7.42–7.27 (m, 5H), 7.12 (d, 2H, J=8.80 Hz),6.88 (d, 2H, J=8.80 Hz), 5.02 (s, 2H), 3.96 (dd, 1H, J=7.83 Hz, J=4.89Hz), 3.47 (hp, 1H, J=5.87 Hz), 2.83 (dd, 1H, J=13.69 Hz, J=4.89 Hz),2.71 (dd, 1H, J=13.69 Hz, J=8.31 Hz), 1.02 (d, 2H, J=5.87 Hz), 0.86 (d,2H, J=5.87 Hz). IR (KBr) 3012, 2977, 2931, 1767, 1722, 1610, 1511, 1380,1240, 1116, 1020. HRMS (TOF ES⁻) m/z exact mass calculated for C₁₉H₂₁O₄(M−1) 13.1440. Found m/z 313.1434.

Example 176A(2S)-2-isopropoxy-3-{4-[3-(4-phenoxy)-phenoxy)-propoxy]phenyl}propanoicacid sodium salt

(S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic-acid ethyl ester

A solution of (S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid (20 g,100 mmol) in 3 A ethanol (140 mL) was treated dropwise with concentratedsulfuric acid (5.7 mL)) and stirred at room temperature overnight. Thesolution was concentrated and is water (110 mL) was added. Sodiumbicarbonate was added to bring the pH to 7–8. The mixture was extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith 20% NaCl solution (50 ml), dried (MgSO₄), filtered, andconcentrated to a golden oil (18 g, 80%). ¹H-NMR (CDCl₃): 7.1(d, 2H);6.7(d, 2H); 4.2(m, 2H); 3.9(m, 1H); 3.6(s, 3H); 2.95(m, 2H); 125(t, 3H).MS (ES): 223.2 (M−1).

(S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid

(S)-2-Hydroxy-3-(4-hydroxy-phenyl)-propionic acid (121 g, 0.664 mol)(Wang et al. Tetrahedron Lett. 1998, 39, 5501) in absolute EtOH (2 L)was treated with potassium carbonate (184 g, 1.33 mol) and benzylchloride 169 g, 1.34 mol). The mixture was heated at reflux overnightand concentrated to about half the volume under vacuum. Aqueous 5N NaOH(100 mL) was added, and the mixture was stirred at ambient temperatureovernight and then concentrated. The residue was acidified withconcentrated HCl. The yellow sold was collected by filtration and driedovernight under vacuum at 50° C. The crude product in isopropanol (1.8L) was heated at reflux for about 30 minutes, cooled to ambienttemperature, and stirred for about 16 hours. The slurry was filtered anddried under vacuum at 70° C. overnight to give the title compound as awhite solid (137 g, 76%).

Step A: (S)-5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one

(S)-3-(4-Benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g, 7.34 mmol),2,2-dimethoxypropane (18.63 g, 0.179 mol) and pyridinium p-toluenesulfonate (0.92 g, 3.66 mmol) in chloroform (80 mL) was heated to refluxfor 40 minutes under N₂. The mixture was cooled, diluted with water, andextracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄) andconcentrated in vacuo to give crude product that was purified by flashchromatography using 10:1 hexanes:acetone to afford the title compound(2.01 g, 88%). ¹H-NMR (400 MHz, CDCl₃) δ 7.43–7.29 (m, 5H), 7.17 (d, 2H,J=8.80 Hz), 6.91 (d, 2H, J=8.80 Hz), 5.04 (s, 2H), 4.61 (dd, 1H, J=6.36Hz, J=4.40 Hz), 3.12 (dd, 1H, J=14.617 Hz, J=4.40 Hz), 2.99 (dd, 1H,J=14.67 Hz, J=6.36 Hz), 1.49 (s, 3H), 1.36 (s, 3H). MS (ES⁺) m/z calc'dfor C₁₉H₂₀O₄ (M+NH₄) 330. Found m/z 330.

Step B: (S)-5-(4-hydroxy-benzyl)-2,2-dimethyl-[1,3]dioxolane-4-one

(S)-5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one (1.0 g, 3.2mmol) was combined with 10% Pd/C (0.75 g) in EtOAc (40 mL) and purgedwith N₂ then H₂ and then stirred under a hydrogen balloon for 3 hours.Sodium sulfate was added, and the mixture was filtered through Celite.The solvent was removed in vacuo to afford the title compound (0.747 g,100%). ¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, 2H, J=8.31 Hz), 6.76 (d, 2H,J=8.31 Hz), 4.93 (bs, 1H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.11(dd, 1H, J=14.67 Hz, J=4.40 Hz), 2.98 (dd, 1H, J=14.67 Hz, J=5.86 Hz),1.49 (s, 3H), 1.36 (s, 3H). MS (ES⁻) m/z mass calc'd for C₁₂H₁₄O₄ (M−1)221. Found m/z 221.

Step C: (S)-3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester

A 0° C. solution of(S)-5-(4-hydroxy-benzyl)-2,2-methyl-[1,3]dioxolan-4-one (0.20 g, 0.90mmol) and triethylsilane (1.05 g, 9.02 mmol) in CH₂Cl₂ (10 mL) wastreated dropwise with TiCl₄ (0.90 mL, 0.90 mmol, 1M CH₂Cl₂) under N₂.The solution was stirred at 0° C. for about 15 min and warmed to roomtemperature. After about 45 minutes, the mixture was quenched with waterand extracted with EtOAc. The organic layer was dried (Na₂SO₂),filtered, and concentrated in vacuo to give of crude product (0.32 g).This material was combined with ethanol (25 mL) and conc. H₂SO₂ (1 mL)and stirred for 17 hours at room temperature under N₂. The mixture wasconcentrated and partitioned between EtOAc and water. The organic layerwas dried (Na₂SO₂), filtered, and concentrated in vacuo. The crudeproduct was purified by flash chromatography using 5:1 hexanes:acetoneto afford the title compound (0.158 g, 70%). ¹H NMR (400 MHz, CDCl₃) δ7.11 (d, 2H, J=8.31 Hz), 6.76 (d, 2H, J=8.31 Hz), 4.79 (bs, 1H),4.20–4.12 (m, 2H), 3.99 (dd, 1H, J=8.56 Hz, J=4.89 Hz), 3.49 (hp, 1H,J=6.36 Hz), 2.94–2.83 (m, 2H), 1.23 (t, 3H, J=6.85 Hz), 1.14 (d, 3H,J=6.36 Hz), 0.96 (d, 3H, J=6.36 Hz). MS (ES⁻) m/z calc'd for C₁₄H₂₀O₄(M−1) 251. Found m/z 251.

Step D:(S)-2-isopropoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid

The synthesis of2S-2-isopropoxy-3-{4-ο3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoicacid sodium salt was completed according to procedures described inExample 171. ¹H NMR (400 MHz, CDCl₃): δ 0.96 (d, 3 H, J=5.9 Hz), 1.09(d, 3 H, J=6.3 Hz), 2.22 (quartet, 2H, J=5.9 Hz), 2.82 (dd, 1 H, J=9.3Hz, 13.7 Hz), 3.01 (dd, 1 H, J=2.5 Hz, 13.7 Hz), 3.43 (q, 1 H, J=5.9Hz), 4.01 (dd, 1 H, J=3.4, 8.8 Hz), 4.11 (q, 4 H, J=6.4 Hz), 6.80 (d, 2H, J=8.3 Hz), 6.88 (d, 2 H, J=8.8 Hz), 6.90–7.00 (m, 4 H), 7.01–7.05 (m,1 H), 7.17 (d, 2 H, J=8.3 Hz), 7.28 (d, 2 H, J=8.8 Hz). MS: 451.2 (MH⁺).

Example 1772-Methoxy-3-{3-methoxy-4-[3-(4-phenylacetyl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid(Example 175, Step B) and 1-(4-Hydroxy-phenyl)-2-phenyl-ethanonefollowing the Standard Procedure J. MS (ES) for C₂₈H₃₀O₇ [M+H]⁺: 479.

Example 1783-{4-[3-(4-Butoxy-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid(Example 175, Step B) and 4-Butoxy-phenol following the StandardProcedure J. MS (ES) for C₂₄H₃₂O₇ [M+Na]⁺: 455.

Example 1792-Methoxy-3-{3-methoxy-4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid(Example 175, Step B) and 6-Hydroxy-2-phenyl-chromen-4-one following theStandard Procedure J. ¹H-NMR (200.15 MHz, CDCl₃): 8.0–7.9 (m, 2H),7.6–7.5 (m, 5H), 7.30 (dd, 1H, J=9.0, 3.0), 6.9–6.8 (m, 4H), 4.3–4.2 (m,4H), 4.00 (dd, 1H, J=7.2, 4.6), 3.83 (s, 3H), 3.41 (s, 3H), 3.09 (dd,1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.2, 7.2), 2.33 (qn, 2H, J=6.2) ppm.

Example 1802-Methoxy-3-(3-methoxy-4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-phenyl)-propionicacid

The title compound was prepared from3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid(Example 175, Step B) and 4-(4-Trifluoromethyl-phenoxy)-phenol followingthe Standard Procedure J. MS (ES) for C₂₇H₂₇F₃O₇ [M+Na]⁺: 543.

Example 1813-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid(Example 175, Step B) and 4-Benzyloxy-phenol following the StandardProcedure J. MS (ES) for C₂₇H₃₀O₇ [M+Na]⁺: 489.

Example 1823-{4-[3-(4-Dibenzofuran-3-yl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid

The title compound was prepared from3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid(Example 175, Step B) and 4-Dibenzofuran-3-yl-phenol following theStandard Procedure J. MS (ES) for C₃₂H₃₀O₇ [M+NH₄]⁺:544, [M+Na]⁺: 549.

Example 183(2S)-3-{4-[4-(Biphenyl-4-yloxy)-butoxy]-phenyl}-2-methoxy-propionic acid

Step A(2S)-3-[4-(4-Hydroxy-butoxy-phenyl]-2-methoxy-propionic acid ethyl ester

A mixture of 3-(4-Hydroxy-phenyl)-2-methoxy-propionic acid ethyl esterand 3-(tert-Butyl-dimethyl-silanyloxy)-butan-1-ol were treated underMitsounobu coupling Standard conditions B using DIAD and THF. Theproduct thus obtained was treated under Standard Procedure E forcleaveage protected alcohols to give the title product.

Step B

(2S)-3-[4-(4-Bromo-butoxy-phenyl]-2-methoxy-propionic acid ethyl ester

The title compound was prepared from(2S)-3-[4-(4-Hydroxy-butoxy)-phenyl]-2-methoxy-propionic acid ethylester and following the procedure described in Example 132, Step D weobtained the title compound.

Step C

(2S)-3-{4-[4-(Biphenyl-4yloxy-butoxy]-phenyl}-2-methoxy-propionic acidethyl ester

The title compound was prepared from(2S)-3-[4-(4-Bromo-butoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Step B) and 4-phenylphenol under the Standard Procedure I to give theproduct.

Step D

2S)-3-{4-[4-(Biphenyl-4-yloxy)-butoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-{4-[4-(Biphenyl-4-yloxy)-butoxy]-phenyl}-2-methoxy-propionic acidethyl ester from Step C under the standard Hydrolysis procedure C.(LiOH). ¹H-NMR (200.15 MHz, CDCl₃): 7.57–7.49 (m, 4H); 7.45–7.37 (m,2H); 7.32–7.11 (m, 3H); 6.97 (d, 2H, J=8.9); 6.84 (d, 2H, J=8.9);4.11–3.93 (m, 5H); 3.40 (s, 3H); 3.10 (dd, 1H, J=14.0, 4.3); 2.96 (dd,1H, J=14.5, 7.0); 1.99–1.97 (m, 4H) ppm.

Example 184(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

The title compound was prepared from(2S)-3-[4-(4-Bromo-butoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 183, Step B) and 4-hydroxybenzophenone under the StandardProcedure I to give the product.

Step B

(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propionicacid ethyl ester from Step A under the Standard hydrolysis procedure C.(LiOH). ¹H-NMR (200.15 MHz; CDCl₃): 7.81 (d, 2H, J=8.9), 7.75 (dd, 2H,J=8.3, 1.4), 7.6–7.4 (m, 3H), 7.15 (d, 2H, J=8.6), 6.81 (d, 2H, J=8.3),4.2–3.9 (m, 5H), 3.37 (s, 3H), 3:08 (dd, 1H, J=14.2, 4.3), 2.94 (dd, 1H,J=14.2, 7.5), 2.1–1.9 (m, 4H) ppm.

Example 185(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propionicacid

Step A(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propionicacid ethyl ester

The title compound was prepared from(2S)-3-[4-(4-Bromo-butoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 183, Step B) and 4-phenoxyphenol under the Standard Procedure Ito give the product.

Step B

(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-butoxy]-phenyl}-propionicacid ethyl ester, from Step A under the Standard hydrolysis procedure C.(LiOH). ¹H-NMR (200.15 MHz, CDCl₃): 7.4–7.2 (m, 2H), 7.15 (d, 2H,J=8.6), 7.1–6.7 (m, 9H), 4.0–3.9 (m, 5H), 3.34 (s, 3H), 3.08 (dd, 1H,J=14.0, 4.0), 2.93 (dd, 1H, J=14.0, 7.8), 2.1–1.9 (m, 4H) ppm.

Example 186(2S)-2-Methoxy-3-{4-[2-(2,3,6-trifluoro-phenoxy)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-phenyl]-2-methoxypropionic acid linked to Wang'sResin (Example 94, Step C) via the Mitsounobu coupling-cleveage(Standard Procedure G) with 2-(2,3,6-Trifluoro-phenoxy)-ethanol to givethe desire product. ¹H-NMR (200.15 MHz, CDCl₃): 7.15 (d, 2H, J=8.6),6.9–6.8 (m, 4H), 4.51 (t, 2H, J=4.0), 4.27 (t, 2H, J=4.8), 3.97 (dd, 1H,J=7.2, 4.3), 3.39 (s, 3H), 3.09 (dd, 1H, J=14.5, 4.5), 2.95 (dd, 1H,J=14.5, 7.5) ppm.

Example 187(2S)-3-[4-(3-Benzyloxy-benzyloxy)-phenyl]-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-phenyl]-2-methoxypropionic acid linked to Wang'sResin (Example 94, Step C) via the Mitsounobu coupling-cleveage(Standard Procedure G) with (3-Benzyloxy-phenyl)-methanol to give thedesire product. ¹H-NMR (200.15 MHz, CDCl₃): 7.5–7.2 (m, 5H), 7.2–6.8 (m,8H), 5.07 (s, 2H), 5.01 (s, 2H), 3.99 (dd, 1H, J=7.0, 4.6), 3.40 (s,3H), 3.10 (dd, 1H, J=14.2, 4.3), 2.96 (ad, 1H, J=14.5, 7.2) ppm.

Example 1883-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-propionicacid

Step A3-[4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-phenyl]-3-hydroxy-2-methoxy-propionicacid methyl ester

A solution of 4-tert-butyldimethylsilanyloxy-2-methoxy benzaldehyde (1eq) and methyl methoxyacetate (1.25 eq) in THF (10 mL) at −78° C. wasadded dropwise to sodium bis(trimethylsilyl)amide (1.25 eq, 1N in THF)at −78° C. The reaction mixture was stirred for 3 h and quenched with 1NHCl (5 mL). The mixture was allowed to warm to room temperature, dilutedwith water (15 mL), and extracted with ethyl acetate (3×15 mL). Thecombined organic layers were dried (MgSO₄) and concentrated. The residuewas purified by silica gel column to obtain the title compound.

Step B

3-[4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-phenyl]-2-methoxy-propionicacid methyl ester

A mixture of3-[4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-phenyl]-3-hydroxy-2-methoxy-propionicacid methyl ester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq) anda catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred atroom temperature over night. The reaction mixture was diluted with etherand washed with HCl 1N. Dried and concentrated in vacuo to give aresidue which was chromatographed in silica gel to yield a compoundwhich was dissolved in methanol was treated with Mg (20 eq) and stirreduntil gas evolution was observed. Cooled to 0° C. and stirred for 4hours. The solvent was removed and the residue reconstituted in etherwashed with HCl 1N and brine and concentrated to give the title product.

Step C

2-(4-Hydroxy-2-methoxy-benzyl)-butyric acid methyl ester

3-[4-(tert-Butyl-dimethyl-silanyloxy)-2-methoxy-phenyl]-2-methoxy-propionicacid methyl ester from Step B was treated under the Standard Procedure Eto cleveage the protected silyl group and obtained the product.

Step D

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-propionicacid

A mixture solution of 2-(4-hydroxy-2-methoxy-benzyl)-butyric acid methylester from Step C and 3-(biphenyl-4-yloxy)-propan-1-ol was reacted underthe Standard Mitsounobu coupling conditions B (DIAD/toluene) to give thecorresponding coupled product, which afforded the title compound via theStandard hydrolysis procedure C (NaOH). MS(ES) for C₂₆H₂₈O₆ [M+NH₄]⁺:454.

Example 1893-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-propionicacid

A mixture solution of 2-(4-Hydroxy-2-methoxy-benzyl)-butyric acid ethylester from Example 188, Step C and[4-(3-Hydroxy-propoxy)-phenyl]-phenyl-methanone were allowed to reactunder the Standard Mitsounobu coupling conditions B (DIAD/toluene) togive the corresponding coupled product which by the Standard hydrolysisprocedure C (NaOH) yield the title compound. MS (ES) for C₂₇H₂₈O₇[M+H]⁺: 465.

Example 1902-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid

A mixture solution of 2-(4-Hydroxy-2-methoxy-benzyl)-butyric acid ethylester from Example 188, Step C and 3-(4-phenoxy-phenoxy)-propan-1-olwere allowed to react under the Standard Mitsounobu coupling conditionsB (DIAD/toluene) to give the corresponding coupled product which by theStandard hydrolysis procedure C (NaOH) yielded the title compound. MS(ES) for C₂₆H₂₈O₇ [M+Na]⁺: 475.

Example 1913-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionicacid

Step A4-Benzyloxy-2-chloro-benzoic acid benzyl ester

A mixture solution of 2-chloro-4-hydroxybenzoic (1 eq) acid with benzylbromide (2 eq) and K₂CO₃ (3 eq) in acetonitrile were heated at 85° C.Then filtered and concentrated to dryness to give after chromatographyin silica gel the title compound.

Step B

(4-Benzyloxy-2-chloro-phenyl)-methanol

A mixture of 4-Benzyloxy-2 chloro-benzoic acid benzyl ester from Step Awith DIBAL-H 1M in toluene (2.2 eq) in THF were stirred at roomtemperature for 3 hours. The quenched with tartrate saturated solutionand extracted with ethyl acetate. Concentrated to dryness and purifiedby chromatography to afford the title compound.

Step C

4-Benzyloxy-2-chloro-benzaldehyde

To a solution of (4-Benzyloxy-2-chloro-phenyl)-methanol indichloromethane, MnO₂ (10 eq) were added and the mixture reactionstirred overnight. Filtered through a pad of celite and purified bychromatography in silica gel to give the title product.

Step D

3-(4-Benzyloxy-2-chloro-phenyl)-3-hydroxy-2-methoxy-propionic acid ethylester

A solution of 4′-Benzyloxy-2-chloro-benzaldehyde (1 eq) and methylmethoxyacetate (1.25 eq) in THF (10 mL) at −78° C. was added dropwise tosodium bis(trimethylsilyl)amide (1.25 eq, 1N in THF) at −78° C. Thereaction mixture was stirred for 3 h and quenched with 1N HCl (5 mL).The mixture was allowed to warm to room temperature, diluted with water(15 mL), and extracted with ethyl acetate (3×15 mL). The combinedorganic layers were dried (MgSO₄) and concentrated. The residue waspurified by silica gel column to obtained the title compound.

Step E

3-(4-Benzyloxy-2-chloro-phenyl)-2-methoxy-propionic acid ethyl ester

A mixture of3-(4-Benzyloxy-2-chloro-phenyl)-3-hydroxy-2-methoxy-propionic acid ethylester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq) and a catalyticamount of DMAP (0.1 eq) in dichloromethane was stirred at roomtemperature over night. The reaction mixture was diluted with ether andwashed with HCl 1N. Dried and concentrated in vacuo to give a residuewhich was chromatographed in silica gel to yield a compound which wasdissolved in methanol was treated with Mg (20 eq) and stirred until gasevolution was observed. Cooled to 0° C. and stirred for 4 hours. Thesolvent was removed and the residue reconstituted in ether washed withHCl 1N and brine and concentrated to give the title product.

Step F

3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester

3-(4-Benzyloxy-2-chloro-phenyl)-2-methoxy-propionic acid ethyl ester inethyl acetate was treated with Pd(C) and H₂ under balloon pressure. Thenfiltered through celite and concentrated to give the title compound.

Step G

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionicacid

A mixture solution of 3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propionicacid ethyl ester from Step F and 3-(Biphenyl-4-yloxy)-propan-1-ol wereallowed to react under the Standard Mitsounobu coupling conditions B(DIAD/toluene) to give the corresponding coupled product which by theStandard hydrolysis procedure C (NaOH) yield the title compound. MS (ES)for C₂₅H₂₅ClO₅ [M+NH₄]⁺: 458.

Example 1923-{2-Chloro-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

A mixture solution of 3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propionicacid ethyl ester from Example 191, Step F and3-(4-phenoxy-phenoxy)-propan-1-ol were allowed to react under theStandard Mitsounobu coupling conditions B (DIAD/toluene) to give thecorresponding coupled product which by the Standard hydrolysis procedureC (NaOH) yield the title compound. MS (ES) for C₂₅H₂₅ClO₆ [M+NH₄]⁺: 474.

Example 1933-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionicacid

A mixture solution of 3-(2-Chloro-4-hydroxy-phenyl)-2-methoxy-propionicacid ethyl ester from Example 132, Step F and[4-(3-Hydroxy-propoxy)-phenyl]-phenyl-methanone were allowed to reactunder the Standard Mitsounobu coupling conditions B (DIAD/toluene) togive the corresponding coupled product which by the Standard hydrolysisprocedure C (NaOH) yield the title compound. MS (ES) for C₂₆H₂₅ClO₆[M+H]⁺: 469.

Example 194(2S)-4-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid

Step A(2S)-4-{3-[4-(2-Ethoxycarbonyl-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoicacid benzyl ester

(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid ethylester from 0, Step B and 4-Hydroxy-benzoic acid benzyl ester weretreated under Mitsounobu Standard coupling conditions B to give thetitle compound.

Step B

(2S)-4-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid

The title compound was prepared from(2S)-4-{3-[4-(2-Ethoxycarbonyl-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoicacid benzyl ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS(ES) for C₂₀H₂₂O₇ [M+Na]⁺: 397.

Example 195(2S)-3-{4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-{4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid ethylester from Example 171, Step B and 4-Dibenzothiophen-4-yl-phenol weretreated under Mitsounobu Standard coupling conditions B to give thetitle compound.

Step B

(2S)-3-{4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-Dibenzothiophen-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS(ES) for C₃₁H₂₈O₅S [M+NH₄]⁺: 530.

Example 196(2S)-3-{4-[3-(4′-Hydroxy-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-(4-{3-[4′-(tert-Butyl-dimethyl-silanyloxy)-biphenyl-4-yloxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A, and4-(tert-Butyl-dimethyl-silanyloxy)-biphenyl-4-ol were treated with CsCO₃(3 eq) in DMF and stirred at room temperature over night.

Filtered and concentrated in vacuo to give the title compound.

Step B

(2S)-3-{4-[3-(4′-Hydroxy-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-{3-[4′-(tert-Butyl-dimethyl-silanyloxy)-biphenyl-4-yloxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS(ES) for C₂₅H₂₆O₆ [M+Na]⁺: 445.

Example 197(2S)-4′-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylicacid

Step A(2S)-4′-{3-[4-(2-Ethoxycarbonyl-2-methoxy-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylicacid methyl ester

(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid ethylester from Example 171, Step B and 4′-Hydroxy-biphenyl-4-carboxylic acidmethyl ester were treated under Mitsounobu Standard coupling conditionsB to give the title compound.

Step B

(2S)-4′-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylicacid

The title compound was prepared from(2S)-4′-{3-[4-(2-Ethoxycarbonyl-2-methoxy-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylicacid methyl ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS(ES) for C₂₆H₂₆O₇ [M+NH₄]⁺: 468, [M+Na]⁺: 473.

Example 198(2S)-3-{4-[2-(4-Benzoyl-phenoxy)-cyclohexyloxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-hydroxyphenyl)-2-methoxy-propionic acid linked to Wang's resinExample 94, Step C) via Mitsounobu coupling (Standard Procedure F) togive 3-[4-(2-Hydroxy-cyclohexyloxy)-phenyl]-2-methoxy-propionic acidlinked to the resin. A second Mitsounobu coupling reaction with4-hydroxybenzophenone via Standard Procedure G allow us to get the titlecompound. ¹H-NMR (CDCl₃, 200 MHz): 7.75 (d, 4H, J=8.6); 7.57–7.43 (m,3H); 7.13 (d, 2H, J=8.9); 6.89 (d, 2H, J=9.1); 6.79 (d, 2H, J=8.6);4.53–4.36 (m, 2H); 4.04–3.99 (m, 1H); 3.43 (s, 3H); 3.08–2.94 (m, 2H);1.38–1.29 (m, 8H) ppm.

Example 199(2S)-3-(4-{2-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclohexyloxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-(4-hydroxyphenyl)-2-methoxy-propionic acid linked to Wang's resin(Example 94, Step C) via Mitsounobu coupling (Standard Procedure F) togive 3-[4-(2-Hydroxy-cyclohexyloxy)-phenyl]-2-methoxy-propionic acidlinked to the resin. A second Mitsounobu coupling reaction with4-fluoro-4′-hydroxybenzophenone via Standard Procedure G allows us toget the title compound. ¹H-NMR (CDCl₃, 200 MHz): 7.83–7.69 (m, 4H);7.19–7.11 (m, 4H); 6.89 (d, 2H, J=8.9); 6.79 (d, 2H, J=8.6); 4.53–4.33(m, 2H); 4.02 (dd, 1H, J=6.5, 4.8); 3.43 (s, 3H); 3.10 (dd, 1H, J=14.4,4.8), 2.98 (dd, 1H, J=14.4, 6.5); 1.38–1.29 (m, 8H) ppm.

Example 200(2S)-3-(4-{3-[3-(4-Fluoro-phenyl)-benzofuran-6-yloxy]-propoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with3-(4-Fluoro-phenyl)-benzofuran-6-ol under the Standard Procedure J. Thecompound thus obtained was allowed to react under Standard hydrolysisprocedure C (NaOH) to give the title compound. MS(ES) for C₂₇H₂₅FO₆[M+NH₄]⁺: 482, [M+Na]⁺: 487, [M+H]⁺: 464.

Example 201(2S)-2-Methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-propoxy]-phenyl}-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with5,6,7,8-Tetrahydro-naphthalen-2-ol under the Standard Procedure J. Thecompound thus obtained was allowed to react under Standard HydrolysisProcedure C (NaOH) to give the title compound. MS(ES) for C₂₃H₂₈NO₅[M+Na]⁺: 407, [M+H]⁺: 385.

Example 202(2S)-3-{4-[3-(4-Benzyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 4-Benzyloxy-phenol under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₈O₆ [M−H]⁻: 435.

Example 203(2S)-3-{4-[3-(4-Butoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 4-Butoxy-phenol under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₃H₃₀O₆ [M+NH₄]⁺: 420, [M+Na]⁺: 425, [M+H]⁺: 403.

Example 204(2S)-3-{4-[3-(4-Heptyloxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 4-Heptyloxy-phenol under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₃₆H₃₆O₆ [M+Na]⁺: 467, [M+H]⁺: 445.

Example 205(2S)-3-{4-[3-(6-Benzoyl-naphthalen-2-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with(6-Hydroxy-naphthalen-2-yl)-phenyl-methanone under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C(NaOH) to give the title compound. MS(ES)for C₃₀H₂₈O₆ [M+Na]⁺: 507, [M+H]⁺: 485.

Example 206(2S)-3-{4-[3-(Benzo[1,3]dioxol-5-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with Benzo[1,3]dioxol-5-ol underthe Standard Procedure J. The compound thus obtained was allowed toreact under Standard hydrolysis procedure C (NaOH) to give the titlecompound. MS(ES) for C₂₀H₂₂O₇ [M+Na]⁺: 397, [M+H]⁺: 375.

Example 207(2S)-3-{4-[3-(9H-Fluoren-2-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 9H-Fluoren-2-ol under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₆O₅ [M+Na]⁺: 441.

Example 208(2S)-2-Methoxy-3-{4-[3-(4-octyl-phenoxy)-propoxy]-phenyl}-propionic acid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 4-Octyl-phenol under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₇H₃₈O₅ [M+Na]⁺: 466.

Example 209(2S)-2-Methoxy-3-{4-[3-(naphthalen-I-yloxy)-propoxy]-phenyl}-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with Naphthalen-1-ol under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₃H₂₄O₅ [M+Na]⁺: 403, [M+H]⁺: 381.

Example 210(2S)-3-{4-[3-(1H-Indol-7-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 1H-Indol-7-ol under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₁H₂₃NO₅ [M+Na]⁺: 392; [M+H]⁺: 370.

Example 211(2S)-3-{4-[3-(4′-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step APreparation of p-Iodophenol Linked to the Wang's Resin

Wang' resin, (1 eq), p-iodophenol (4.5 eq) and PPh₃ (5–8 eq) weresuspended in a vial and cooled to 0° C. then DIAD was added (5 eq). Themixture reaction was allowed to get room temperature and stirredovernight. Filtered of and washed with MeOH—CH₂Cl₂-THF—HClaq and CH₂Cl₂to give the product.

Step B

4′-Fluoro-biphenyl-4-ol

A mixture of p-Iodophenol linked to the Wang's resin from Step A (1 eq),4-fluorobenzene boronic acid (6 eq), K₂CO₃ (12 eq) and Pd(OAc)₂ (0.5 eq)were suspended in a mixture of dioxane/water (6/1) and the mixture washeated at 100° C. and stirring for 36 hours. The resin was washed withDMF/H₂O and MeOH/THF/HCl diluted and MeOH/CH₂Cl₂. After it was dried,was suspended in dichloromethane, and TFA 95% was added. The mixture wasstirred at room temperature for 30 min then filtered and washed withMeOH and dichloromethane. The solvents were concentrated to dryness togive the title product.

Step C

(2S)-3-{4-[3-(4′-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 4′-Fluoro-biphenyl-4-ol fromStep B under the Standard Procedure J. The compound thus obtained wasallowed to react under Standard hydrolysis procedure C (NaOH) to givethe title compound. MS(ES) for C₂₅H₂₅FO₅ [M+NH₄]⁺: 442, [M+Na]⁺: 447.

Example 212(2S)-3-{4-[3-(4′-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A4-chlorobiphenyl-4-ol

The title compound was prepared following the procedure described inExample 211, Step B with 4-chlorophenyl boronic acid.

Step B

(2S)-3-{4-[3-(4′-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with chloro-biphenyl-4-ol from StepA under the Standard Procedure J. The compound thus obtained was allowedto react under Standard hydrolysis procedure C (NaOH) to give the titlecompound. MS(ES) for C₂₅H₂₅ClO₅ [M+Na]⁺: 463, [M+H]⁺: 441.

Example 213(2S)-3-{4-[3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A3′,5′-Bis-trifluoromethyl-biphenyl-4-ol

The title compound was prepared following the procedure described inExample 211, Step B with 3,5-bis(trifluoromethyl)-phenyl boronic acid.

Step B

(2S)-3-{4-[3-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with3′,5′-Bis-trifluoromethyl-biphenyl-4-ol from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₇H₂₄F₆O₅ [M+Na]⁺: 565, [M+H]⁺: 543.

Example 214(2S)-3-{4-[3-(4-Dibenzofuran-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A4-Dibenzofuran-4-yl-phenol

The title compound was prepared following the procedure described inExample 211, Step B with 4-benzofurane boronic acid.

Step B

(2S)-3-{4-[3-(4-Dibenzofuran-4-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom 0, Step A was treated with 4-Dibenzofuran-4-yl-phenol from Step Aunder the Standard Procedure J. The compound thus obtained was allowedto react under Standard hydrolysis procedure C (NaOH) to give the titlecompound. MS(ES) for C₃₁H₃₀O₆ [M+Na]⁺: 519.

Example 215(2S)-2-Methoxy-3-{4-[3-(4′-phenoxy-biphenyl-4-yloxy)-propoxy]-phenyl}-propionicacid

Step A4′-phenoxy-biphenyl-4-ol

The title compound was prepared following the procedure described inExample 211, Step B with 4-phenoxyphenyl boronic acid.

Step B

(2S)-2-Methoxy-3-{4-[3-(4′-phenoxy-biphenyl-4-yloxy)-propoxy]-phenyl}-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 4′-phenoxy-biphenyl-4-ol fromStep A under the Standard Procedure J. The compound thus obtained wasallowed to react under Standard hydrolysis procedure C (NaOH) to givethe title compound. MS(ES) for C₃₁H₃₀O₆ [M+NH₄]⁺: 516, [M+Na]⁺: 521.

Example 216(2S)-2-Methoxy-3-{4-[3-(4-thiophen-2-yl-phenoxy)-propoxy]-phenyl}-propionicacid

Step A4-Thiophen-2-yl-phenol

The title compound was prepared following the procedure described inExample 211, Step B with tiophene-2-boronic acid.

Step B

(2S)-2-Methoxy-3-{4-[3-(4-thiophen-2-yl-phenoxy)-propoxy]-phenyl}-propionicacid

2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 4-Thiophen-2-yl-phenol fromStep A under the Standard Procedure J. The compound thus obtained wasallowed to react under Standard hydrolysis procedure C (NaOH) to givethe title compound. MS(ES) for C₂₃H₂₄O₅S [M+NH₄]⁺: 430, [M+Na]⁺: 435.

Example 217(2S)-3-{4-[3-(3′-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A3′-Chloro-biphenyl-4-ol

The title compound was prepared following the procedure described inExample 211, Step B with 3-chlorophenyl boronic acid.

Step B

(2S)-3-{4-[3-(3-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom 0, Step A was treated with 3′-Chloro-biphenyl-4-ol from Step Aunder the Standard Procedure J. The compound thus obtained was allowedto react under Standard hydrolysis procedure C (NaOH) to give the titlecompound. MS(ES) for C₂₅H₂₅ClO₅ [M+NH₄]⁺: 458, [M+Na]⁺: 463.

Example 218(2S)-3-{4-[3-(2′-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A2′-Chloro-biphenyl-4-ol

The title compound was prepared following the procedure described inExample 211, Step B with 2-chlorophenyl boronic acid

Step B

(2S)-3-{4-[3-(2′-Chloro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 2-Chloro-biphenyl-4-ol fromStep A under the Standard Procedure J. The compound thus obtained wasallowed to react under

Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₅H₂₅ClO₅ [M+NH₄]⁺: 458, [M+Na]⁺: 463.

Example 219(2S)-3-{4-[3-(2′-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A2′-Fluoro-biphenyl-4-ol

The title compound was prepared following the procedure described inExample 211, Step B with 2-fluorophenyl boronic acid

Step B

(2S)-3-{4-[3-(2′-Fluoro-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 2-fluoro-biphenyl 4 from StepA under the Standard Procedure J. The compound thus obtained was allowedto react under Standard hydrolysis procedure C (NaOH) to give the titlecompound. MS(ES) for C₂₅H₂₅FO₅ [M+NH₄]⁺: 442, [M+Na]⁺: 447.

Example 220(2S)-3-{4-[3-(4-Benzo[1,3]dioxol-5-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A4-Benzo[1,3]dioxol-5-yl-phenol

The title compound was prepared following the procedure described inExample 211, Step B with 3,4-methylenedioxophenyl boronic acid

Step B

(2S)-3-{4-[3-(4-Benzo[1,3]dioxol-5-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 4-Benzo[1,3]dioxol-5-yl-phenolfrom Step A under the Standard Procedure J. The compound thus obtainedwas allowed to react under Standard hydrolysis procedure C (NaOH) togive the title compound. MS(ES) for C₂₆H₂₆O₇ [M+NH₄]⁺: 468, [M+Na]⁺:473.

Example 221(2S)-3-{4-[3-(4′-tert-Butyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A4′-tert-Butyl-biphenyl-4-ol

The title compound was prepared following the procedure described inExample 211, Step B with 4-tert-butylphenyl boronic acid

Step B

(2S)-3-{4-[3-(4′-tert-Butyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with 4′-tert-Butyl-biphenyl-4-olfrom Step A under the Standard Procedure J. The compound thus obtainedwas allowed to react under Standard hydrolysis procedure C (NaOH) togive the title compound. MS(ES) for C₂₉H₃₄O₅ [M+NH₄]⁺: 480, [M+Na]⁺:485.

Example 222(2S)-2-Methoxy-3-{4-[3-(3′-trifluoromethoxy-biphenyl-4-yloxy)-propoxy]-phenyl}-propionicacid

Step A3′-Trifluoromethoxy-biphenyl-4-ol

The title compound was prepared following the procedure described inExample 211, Step B with 3-trifluoromethoxybenzebe boronic acid

Step B

(2S)-2-Methoxy-3-{4-[3-(3′-trifluoromethoxy-biphenyl-4-yloxy)-propoxy]-phenyl}-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with3′-Trifluoromethoxy-biphenyl-4-ol from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₅F₃O₆ [M+Na]⁺: 513, [M+H]⁺: 491.

Example 223(2S)-2-Methoxy-3-{4-[3-(4′-trifluoromethoxy-biphenyl-4-yloxy)-propoxy]-phenyl}-propionicacid

Step A4′-Trifluoromethoxy-biphenyl-4-ol

The title compound was prepared following the procedure described inExample 211, Step B with 4-trifluoromethoxybenzebe boronic acid

Step B

(2S)-2-Methoxy-3-{4-[3-(4′-trifluoromethoxy-biphenyl-4-yloxy)-propoxy]-phenyl}-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with4′-Trifluoromethoxy-biphenyl-4-ol from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₅F₃O₆ [M+NH₄]⁺: 508, [M+Na]⁺: 513.

Example 224(2S)-3-(4-{3-[4-(2-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step Ap-Aminophenol Linked to Wang's Resin

A suspension of Wang's resin in THF/CH₂Cl₂ was treated with DIAD (5 eq),Ph3P (5 eq) and p-nitrophenol (5 eq). The mixture was stirred overnightand then the resin was filtered through and washed with MeOH/CH₂Cl₂several times. After dried the resin was suspended in DAD and treatedwith SnCl2 (10 eq) and stirred again overnight. Filtered and washed withMeOH/CH₂Cl₂ several times and dried to give th product.

Step B

2-Chloro-N-(4-hydroxy-phenyl)-benzamide

A suspension of p-aminophenol linked to the Wang's resin from Step A (1eq) in dichloromethane was treated with triethylamine (2 ml/mmol) and2-chloro-benzoyl chloride (10 eq). The mixture reaction was stirred for1 hour and then the resin was filtered, washed with MeOH/CH₂Cl₂ severaltimes and dried. The resin was then treated with TEA 95% H₂O 5% andstirred at room temperature for 30 minutes. Filtered and washed withdichloromethane/methanol and concentrated to dryness to afford the titlecompound.

Step C

(2)-3-{3-[4-(2-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with2-Chloro-N-(4-hydroxy-phenyl)-benzamide from Step B under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₆ClNO₆ [M+H]⁺: 484.

Example 225(2S)-2-Methoxy-3-(4-{3-[4-(2-methoxy-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionicacid

Step AN-(4-Hydroxy-phenyl)-2-methoxy-benzamide

The title compound was prepared following the procedure described in 0,Step B with 2-methoxy-benzoyl chloride.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(2-methoxy-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethylester, from Example 173, Step A was treated withN-(4-Hydroxy-phenyl)-2-methoxy-benzamide from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₇H₂₉NO₇ [+H]⁺: 480.

Example 226(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step AN-(4-Hydroxy-phenyl)-2,2-dimethyl-propionamide

The title compound was prepared following the procedure described inExample 224, Step B with 2,2-Dimethyl-propionyl chloride.

Step B

(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated withN-(4-Hydroxy-phenyl)-2,2-dimethyl-propionamide from Step A under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₄H₃₁NO₆ [M+H]⁺: 430.

Example 227(2S)-3-(4-{3-[4-(3-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step A3-Fluoro-N-(4-hydroxy-phenyl)benzamide

The title compound was prepared following the procedure described inExample 224, Step B with 3-Fluoro-benzoyl chloride.

Step B

(2S)-3-(4-{3-[4-(3-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with3-Fluoro-N-(4-hydroxy-phenyl)-benzamide from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₆FNO₆ [M+H]⁺: 468.

Example 228(2S)-2-Methoxy-3-(4-{3-[4-(4-(3-methoxy-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionicacid

Step AN-(4-Hydroxy-phenyl)-3-methoxy-benzamide

The title compound was prepared following the procedure described inExample 224, Step B with 3-methoxy-benzoyl chloride.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated withN-(4-Hydroxy-phenyl-3-methoxy-benzamide from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C NaOH) to give the title compound. MS(ES)for C₂₇H₂₉NO₇ [M+H]⁺: 480.

Example 229(2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionicacid

Step AN-(4-Hydroxy-phenyl)-3-methyl-benzamide

The title compound was prepared following the procedure described inExample 224, Step B with 3-methyl-benzoyl chloride.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-benzoylamino-phenoxy]-propoxy}-phenyl)-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated withN-(4-Hydroxy-phenyl)-3-methyl-benzamide from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₇H₂₉NO₆ [M+H]⁺: 464.

Example 230(2S)-3-(4-{3-[4-(4-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step A4-Fluoro-N-(4-hydroxy-phenyl)-benzamide

The title compound was prepared following the procedure described inExample 224, Step B with 4-Fluoro benzoyl chloride.

Step B

(2S)-3-(4-{3-[4-(4-Fluoro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromopropoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with4-Fluoro-N-(4-hydroxy-phenyl)-benzamide from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₆FNO₆ [M+H]⁺: 468.

Example 231(2S)-3-(4-{3-[4-(4-Chloro-benzoylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step A4-Chloro-N-(4-hydroxy-phenyl)-benzamide

The title compound was prepared following the procedure described inExample 224, Step B with 4-chloro-benzoyl chloride.

Step B

(2S)-3-(4-{3-[4-(4-Chloro-benzylamino)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with4-chloro-N-(4-hydroxyphenyl)benzamide from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₆ClNO₆ [M+H]⁺: 484.

Example 232(2S)-2-Methoxy-3-(4-{3-[4-(4-methoxy-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionicacid

Step AN-(4-Hydroxy-phenyl)-4-methoxy-benzamide

The title compound was prepared following the procedure described inExample 224, Step B with 4-methoxy-benzoyl chloride.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(4-methoxy-benzoylamino)-phenoxy]-propoxy}-phenyl)-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with4-methoxy-N-4-hydroxy-phenyl)benzamide from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₇H₂₉NO₇ [M+H]⁺: 480.

Example 233(2S)-2-Methoxy-3-{4-[3-(4-phenylacetylamino-phenoxy)-propoxy]-phenyl}-propionicacid

Step AN-(4-Hydroxy-phenyl)-2-phenyl-acetamide

The title compound was prepared following the procedure described inExample 224, Step B with Phenyl-acetyl chloride.

Step B

(2S)-2-Methoxy-3-{4-[3-(4-phenylacetylamino-phenoxy)-propoxy]-phenyl}-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated withN-(4-Hydroxy-phenyl)-2-phenyl-acetamide from Step A under the StandardProcedure J. The compound thus obtained was allowed to react underStandard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₇H₂₉NO₆ [M+H]⁺: 484.

Example 234(2S)-3-(4-{3-[4-(2-Chloro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step A4-Tributylstannanyl-Phenol Linked to Wang's Resin

p-Iodophenol linked to Wang's resin from Example 211, Step A, wassuspended in toluene and bis-tributyltin was added (5 eq). The mixturereaction was stirred at 100° C. overnight. Then filtered through and theresin was washed with CH₂Cl₂/MeOH/Hexane/MeOH/CH₂Cl₂ to give thecompound.

Step B

(2-Chloro-phenyl)-(4-hydroxy-phenyl)-methanone

4-Tributylstannanyl-phenol linked to Wang's resin from Step A (1 eq),Pd₂(dba)₃ (0.3 eq) and K₂CO₃ (70 mg) were suspended inTHF/Diisopropilmethylamine. To this mixture 2-chloro-benzoyl chloridewas added and stirred for 2 hours. The suspension was filtered and theresin washed with MeOH/CH₂Cl₂/DMF, then HCl diluted/dioxane and Na₂CO₃5%(dioxane) and DMF/MeOH/CH₂Cl₂. Once the resin was dried TFA 95% andCH₂Cl₂ were added and the mixture stirred at room temperature for 30min. The resin was filtered and washed with MeOH/CH₂Cl₂. The solventswere collected and concentrated to dryness to give the title product.

Step C

(2S)-3-(4-{3-[4-(2-Chloro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with(2-Chloro-phenyl)-(4-hydroxy-phenyl)-methanone from Step B under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₅ClO₆ [M+NH₄]⁺: 491, [M+H]⁺: 469.

Example 235(2S)-2-Methoxy-3-(4-{3-[4-(naphthalene-1-carbonyl)-phenoxy]-propoxy}-phenyl)-propionicacid

Step A(4-Hydroxy-phenyl)-naphthalen-1-yl-methanone

The title compound was prepared following the procedure described inExample 234, Step B with naphthalene-1-carbonyl chloride.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(naphthalene-1-carbonyl)-phenoxy]-propoxy}-phenyl)-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A wag treated with(4-Hydroxy-phenyl)-naphthalen-1-yl-methanone from Step A under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₃₀H₂₈O₆ [M+NH₄]⁺: 507, [M+H]+485.

Example 236(2S)-3-(4-{3-[4-(3-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl-2-methoxy-propionicacid

Step A(3-Fluoro-phenyl)-(4-hydroxy-phenyl)-methanone

The title compound was prepared following the procedure described inExample 234, Step B with 3-Fluoro-benzoyl chloride.

Step B

(2S)-3-(4-{3-[4-(3-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with(3-Fluoro-phenyl)-(4-hydroxy-phenyl)-methanone from Step A under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₆H₂₅FO₆ [M+H]⁺: 453.5.

Example 237(2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-propionicacid

Step A(4-Hydroxy-phenyl)-(3-methoxy-phenyl)-methanone

The title compound was prepared following the procedure described inExample 234, Step B with 3-methoxy-benzoyl chloride.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(3-methoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with(4-Hydroxy-phenyl)-(3-methoxy-phenyl)-methanone from Step A under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₇H₂₈O₇ [M+H]⁺: 465.

Example 238(2S)-2-Methoxy-3-(4-{3-[4-(naphthalen-2-carbonyl)-phenoxy]-propoxy}-phenyl)-propionicacid

Step A(4-Hydroxy-phenyl)-naphthalen-2-yl-methanone

The title compound was prepared following the procedure described inExample 234, Step B with naphtalene-2-carbonyl chloride.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(naphthalene-2-carbonyl)-phenoxy]-propoxy}-phenyl)-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with(4-Hydroxy-phenyl)-naphthalen-2-yl-methanone from Step A under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₃₀H₂₈O₆ [M+H]⁺: 485.

Example 239(2)-2-Methoxy-3-(4-{3-[4-(4-methyl-benzoyl)-phenoxy]-propoxy}-phenyl)-propionicacid

Step A(4-Hydroxy-phenyl)-p-tolyl-methanone

The title compound was prepared folowing the procedure described inExample 234, Step B with 4-mehyl-benzoyl chloride.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(4-methyl-benzoyl)-phenoxy]-propoxy}-phenyl)-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with(4Hydroxy-phenyl)-p-tolyl-methanone from Srep A under the StandarProcedure J. The compound thus obtained was allowed to react underStandar hydrolysis procedure C (NaOH) to give the title compound. Ms(ES)for C₂₇H₂₈O₆ [M+NH₄]⁺: 471 [M+H]⁺: 449.

Example 240(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step A1-(4-Hydroxy-phenyl)-2,2-dimethyl-propan-1-one

The title compound was prepared following the procedure described inExample 234, Step B with 2,2-Dimethyl-propionyl chloride.

Step B

(2S)-3-(4-{3-[4-(2,2-Dimethyl-propionyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with1-(4-Hydroxyphenyl)-2,2-dimethyl-propan-1-one from Step A under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₄H₃₀O₆ [M+NH₄]⁺: 437 [M+H]⁺: 415.

Example 241(2S)-3-{4-[3-(4-Isobutyryl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A1-(4-Hydroxy-phenyl)-2-methyl-propan-1-one

The title compound was prepared following the procedure described inExample 234, Step B with Isobutyryl chloride.

Step B

(2S)-3-{4-[3-(4-Isobutyryl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with1-(4-Hydroxy-phenyl)-2-methyl-propan-1-one from Step A under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₃H₂₈O₆ [M+NH₄]⁺: 423 [M+H]⁺: 401.

Example 242(2S)-2-Methoxy-3-(4-{3-[4-(3-phenyl-propionyl)-phenoxy]-propoxy}-phenyl)-propionicacid

Step A1-(4-Hydroxy-phenyl)-3-phenyl-propan-1-one

The title compound was prepared following the procedure described inExample 234, Step B with 3-Phenyl-propionyl chloride.

Step B

(2S)-2-Methoxy-3-(4-{3-[4-(3-phenyl-propionyl)-phenoxy]-propoxy}-phenyl)-propionicacid

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterfrom Example 173, Step A was treated with1-(4-Hydroxy-phenyl)-3-phenyl-propan-1-one from Step A under theStandard Procedure J. The compound thus obtained was allowed to reactunder Standard hydrolysis procedure C (NaOH) to give the title compound.MS(ES) for C₂₈H₃₀O₆ [M+NH₄]⁺: 485 [M+H]⁺: 463.

Example 2433-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionicacid

Step A2-Fluoro-4-hydroxy-benzaldehyde

2-Fluoro-4-methoxy-benzaldehyde (1 g, 6.49 mmol) was added to asuspension of anhydrous potassium iodide (2.15 g, 13 mmol) and aluminumtrichloride (1.04 g, 7.8 mmol) in anhydrous toluene (10 mL), and themixture was stirred at 40° C. for 3 hours. Aluminum trichloride (2.15 g,13 mmol) and anhydrous potassium iodide (0.86 g, 6.49 mmol) were added,and the mixture was stirred for 3 hours. The mixture was diluted withwater (10 mL) and extracted with ethyl acetate (5×20 mL). The combinedorganic layers were dried (MgSO₄), filtered, and concentrated undervacuum. The residue was purified by silica gel chromatography (silicagel, hexanes/ethyl acetate 4:1) to give 2-fluoro-4-hydroxy-benzaldehydeas a white solid (260 mg, 29%). ¹H NMR (200 MHz, Acetone-d₆): δ 10.08(s, 1H), 9.77 (b, 1H), 7.69 (t, 1H, J=8.4), 6.78 (dd, 1H, J=8.8, 2.6),6.65 (dd, 1H, J=12.5, 2.2)ppm.

Step B

4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-benzaldehyde

Potassium tert-butoxide (0.217 g, 1.93 mmol) was added to a solution of2-fluoro-4-hydroxy-benzaldehyde (0.246 g, 1.76 mmol) in anhydrous DMF (5mL) at 0° C., and the mixture was stirred for 30 min.4-(3-Bromo-propoxy)-biphenyl (0.564 g, 1.93 mmol, Example 132, Step D)was added, and the mixture stirred at room temperature for 24 hours. Thereaction mixture was diluted with water and extracted with EtOAc (5×15mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (silica gel, hexanes/ethyl acetate 4:1) to give4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-benzaldehyde as a white solid(540 mg, 88%). ¹H NMR (200 MHz, CDCl₃): δ 10.19 (s, 1H), 7.80 (t, 1H,J=8.4); 7.55–7.48 (m, 4H); 7.42–7.27 (m, 3H); 6.99–6.93 (m, 2H); 6.78(dd, 1H, J=8.8, 2.6); 6.64 (dd, 1H, J=12.4, 2.2); 4.27–4.15 (m, 4H);2.30 (qn, 2H, J=5.9)ppm.

Step C

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-3-hydroxy-2-methoxy-propionicacid methyl ester

A solution of 4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-benzaldehyde(0.320 g, 0.91 mmol) and methyl methoxyacetate (0.099 mL, 1 mmol) in THF(10 mL) at −78° C. was added dropwise to sodium bis(trimethylsilyl)amide(1 mL, 1 mmol, 1N in THF) at −78° C. The reaction mixture was stirredfor 3 hours, quenched with 1N HCl (1 mL), and allowed to warm to roomtemperature. The mixture was diluted with water (10 mL) and extractedwith ethyl acetate (3×30 mL). The combined organic layers were dried(MgSO₄), filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography (silica gel, hexanes/ethyl acetate2:1) to give a 1:1 diastereomeric mixture of3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-3-hydroxy-2-methoxy-propionicacid methyl ester as a white solid (250 mg, 60%). ¹H NMR (200 MHz,CDCl₃): 7.55–7.47 (m, 4H), 7.42–7.23 (m, 4H), 6.95 (d, 2H, J=8.4),6.73–6.66 (m, 1H), 6.59 (dd, 1H, J=12.4, 2.6), 5.19 (dd, 1H, J=15.4,4.8), 4.18–4.04 (m, 4H), 3.93 (d, 1H, J=5.1), 3.68 and 3.63 (2 s, 3H),3.39 and 3.37 (2 s, 3H), 3.12 (b, 1H), 2.24 (qn, 2H, J=6.2)ppm.

Step D

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionicacid methyl ester

Trifluoroacetic anhydride (0.043 mL, 0.37 mmol) and pyridine (0.074 mL,0.93 mmol) were added to a solution of3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-3-hydroxy-2-methoxy-propionicacid methyl ester (0.142 g, 0.31 mmol) in methylene chloride (1 mL) at0° C. The resulting mixture was stirred for 4 hours at room temperatureand was concentrated under vacuum. The residue was dissolved in ethylacetate (50 mL) and 10% palladium on carbon (0.064 g) was added to thesolution. The mixture was stirred under hydrogen pressure (5 atm) for 16hours. The mixture was filtered through celite and concentrated undervacuum. The residue was purified by silica gel chromatography (silicagel, hexanes/ethyl acetate 4:1) to give3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionicacid methyl ester as a white solid (30 mg, 22%). ¹H NMR (200 MHz,CDCl₃): 7.60–7.50 (m, 4H); 7.46–7.27 (m, 3H); 7.18–7.09 (m, 1H);7.03–6.96 (m, 2H); 6.70–6.61 (m, 2H); 4.17 (dt, 4H, J=9.1, 6.2); 4.00(dd, 1H, J=7.3, 5.9); 3.74 (s, 3H); 3.37 (s, 3H); 3.13–2.93 (m, 2H);2.28 (qn, 2H, J=6.2).

Step E

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionicacid

1N aqueous lithium hydroxide solution (1.37 mL) was added to a solutionof3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionicacid methyl ester (0.075 g, 0.17 mmol) in THF (2 mL) at roomtemperature. The reaction mixture was stirred overnight, diluted withwater (10 mL), and extracted with diethyl ether (3×20 mL). The aqueouslayer was acidified with 1N HCl to pH 1 and extracted with ethyl acetate(3×25 mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated to give3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionicacid as a white solid (60 mg, 83%). ¹H-NMR (200 MHz, CDCl₃): 7.56–7.29(m, 7H), 7.18–7.09 (m, 1H), 6.98 (d, 2H, J=8.6), 6.66–6.60 (m, 2H), 4.17(dt, 4H, J=8.9, 5.9), 4.03 (dd, 1H, J=6.7, 4.8), 3.40 (s, 3H), 3.23–3.14(m, 1H), 2.97 (dd, 1H, J=14.0, 6.7), 2.26 (q, 2H, J=5.9)ppm.

Example 244 2-phenoxy-3-[4-(4-phenoxy-phenoxy)-propoxyphenyl]propanoicacid

Step A1-(3-bromopropoxy)-4-phenoxybenzene

The title compound was prepared from 4-phenoxyphenol following the sameprocedure as in Example 132, Step D. ¹H-NMR (200.15 MHz, CDCl₃): δ7.35–7.25 (m, 2H), 7.09–6.87 (m, 7H), 4.10 (t, 2H, J=5.9), 3.62 (t, 2H,J=6.1), 2.55–2.21 (m, 2H)ppm.

Step B

4-Benzyloxyphenyl-2-hydroxypropanoic acid methyl ester

A solution of DL-4-hydroxyphenyllactic acid (0.5 g, 2.74 mmol) wasstirred over night in MeOH/HCl saturated solution. The reaction wasconcentrated to dryness and the crude product (0.545 g, 2.7 mmol) wastreated with K₂CO₃ (3 eq.) and benzyl bromide (0.507 g, 2.97 mmol) inacetonitrile (20 ml) and refluxed overnight. The crude reaction wasfiltered off and concentrated to produce a crude product. The residuewas purified by chromatography (silca-gel, hexanes/Ethyl acetate (3:1)to give a white oil (97%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.43–7.35 (m,5H), 7.14 (d, 2H, J=8.59), 6.92 (d, 2H, J=8.59), 5.04 (s, 2H), 4.42 (dd,1H, J=10.7, 6.1), 2.97 (ddd, 2H, J=4.5, 13.9, 31.1), 2.73 (d, 1H,J=6.1).

Step C

4-Benzyloxyphenyl-2-(4-chlorophenoxy)propanoic acid methyl ester

A solution of triphenylphosphin(0.1 g, 0.38 mmol) in 5 ml of dry THF wastreated at 0° C. with DEAD (0.066 g, 0.38 mmol) and stirred over 30 min.Then a solution of 4-Benzyloxyphenyl-2-hydroxypropanoic acid methylester (0.1 g, 0.35 mmol) and p-chlorophenol (0.048 g, 0.38 mmol) in 2 mlof THF was added to the solution and the mixture reaction was stirred atroom temperature overnight. The mixture was concentrated to dryness andchromatographed in silicagel (hexanes/Ethyl acetate 3:1) to give 0.082 gof product (60%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.46–7.31 (m, 5H),7.28–7.13 (m, 4H), 6.93 (d, 2H, J=8.8), 6.75 (d, 2H, J=8.8), 5.04 (s,2H), 4.73(t, 1H, J=6.1), 3.71 s (s, 3H), 3.18 (d, 2H, J=6.4).

Step D

4-Hydroxyphenyl-2-phenoxypropanoic acid methyl ester

A solution of 4-Benzyloxyphenyl-2-(4-chlorophenoxy)propanoic acid methylester in ethanol with 10% Pd/C (5 wt %) was stirred under hydrogenatmosphere (1 tm) over 2 hours. The catalyst was removed via filtrationthrough a pad of celite and the filtrated concentrated in vacuo toproduce the title compound (90%). ¹H-NMR (200.15 MHz, CDCl₃): δ7.25–7.14 (m, 4H), 7.94–7.73 (m, 4H), 4.81–4.69 (m, 1H), 3.70 (s, 3H),3.16 (d, 2H, J=4.1).

Step E

2-phenoxy-3-[4-(4-phenoxy phenoxy)propoxyphenyl]propanoic acid methylester

A mixture of 3-(4-hydroxyphenyl)-2-phenoxypropanoic acid methyl ester(0.055 g, 0.18 mmol) with 1-(3-bromopropoxy)-4-phenoxybenzene (Step A)(0.055 g, 0.18 mmol) and potassium tert-butoxide (0.020 g, 0.18 mmol)were stirred in DMF (5 mL) overnight. The mixture reaction concentratedin vacuo with toluene (2 times), reconstituted in Ethyl acetate andwashed with water (3 times) and brine, dryed (Na₂SO₄) and concentratedto afford a crude product that was purified by chromatographied insilicagel (hexanes/Ethyl acetate, 3:1) to give 0.022 g of the titlecompound (23%). ¹H-NMR (200.15 MHz, CDCl₃): δ 7.34–7.15 (m, 6H),7.07–6.71 (m, 12H), 4.80–4.68 (m, 1H), 4.13 (t, 4H, J=15.1), 3.71 (s,3H), 3.20–3.15 (m, 2H), 2.30–2.18 (q, 2H).

Step F

2-phenoxy-3-[4-(4-phenoxy phenoxy)propoxphenyl]propanoic acid

The title compound was prepared from 2-phenoxy-3-[4-(4-phenoxyphenoxy)propoxyphenyl]propanoic acid methyl ester (0.022 g, 0.04 mmol).That was stirred with an excess of LiOH 3N (5 eq.) in THF (3 ml)overnight. The solution was acidulate with HCl 1N (to pH 1–2) andextracted with ethyl acetate. The organic layer was dried (Na₂SO₄) andconcentrated under vacuum to produce an oily solid (80%). ¹H-NMR (200.15MHz, CDCl₃): δ 7.33–7.16 (m, 6H), 7.03–6.70 (m, 12H), 4.84–4.71 (m, 1H),4.13 (t, 4H, J=6.1), 3.24–3.19 (m, 2H)ppm.

Example 245(2S,2′S)-3-(4-{3-[4-(2′-Carboxy-2′-methoxy-ethyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

A mixture of (2S)-3-[4-(3-hydroxy-phenyl]-2-methoxypropionic acid ethylester (2 eq), and propylene glycol (1.3 eq) were allowed to react underthe Standard Mitsounobu coupling conditions B (DIAD/Toluene), and theresulting product of this reaction was treated following the Standardhydrolysis conditions C to give the title compound. MS(ES) for C₂₃H₂₈O₈[M+NH₄]⁺: 450, [M+H]⁺: 433.

Example 246 Synthesis of α-Methoxycinnamate Intermediate, ethyl(2S)-2-methoxy-3-(4-hydorxphenyl)propanoate (e)

Step 1a: methyl 3-hydroxy-2-methoxy-3-[4(phenylmethoxy)phenyl]propanoate(a)

Sodium bis-(trimethylsilyl)amide (440 mL 0.44 mol 1.0 M in THF) wascooled to −70° C. under a nitrogen atmosphere. A solution of4-benzyloxybenzaldehyde (85 g, 0.4 mol) and methyl methoxyacetate (52 g,0.5 mol) in THF (0.5 L) was added dropwise at −70° C. over 2 hours, andthe mixture was stirred for an hour. A solution of concentrated HCl (85mL) and water (85 mL) was added at −70° C. The resulting solution wasallowed to warm to ambient temperature and was extracted with MTBE(2×0.5 L). The combined extracts were washed with brine (0.5 L), dried(MgSO₄), filtered, and concentrated under to give 133 g of a red oil.

Step 1b and Step 1c: methyl 3-(4-hydroxyphenyl)-2-methoxypropanoate (b)

Methyl 3-hydroxy-2-methoxy-3-[4-(phenylmethoxy)phenyl]propanoate (133 g,crude from above) was dissolved in CH₂Cl₂ (700 mL), and pyridine (129mL, 1.6 mol) was added. The resulting solution was cooled in a waterbath and trifluoroacetic anhydride (85 mL, 0.6 mol) was added dropwiseunder nitrogen. The bath was removed, and the mixture was stirred atambient temperature for 16 hours. The solution was cooled to 0° C. andconcentrated HCl (150 mL) in water (1 L) was added dropwise. The organiclayer was separated and concentrated, and ethyl acetate (0.5 L) wasadded. The resulting solution was treated with hydrogen gas under 50 psiin the presence of 5% Pd—C (80 g, 50% water wet) at ambient temperaturefor 16 hours. The catalyst was filtered, and the filtrate wasconcentrated under vacuum to give 122 g oil. ¹H-NMR (CDCl₃): 7.1 (2H,d); 6.7 (d, 2H); 5.4 (s, 1H); 4.0 (m, 1H); 3.7 (s, 3H); 3.4 (s, 3H); 3.0(m, 1H). MS (ES)=209.2 (M−1).

Step 1d: 3-(4-hydroxphenyl)-2-methoxypropanoic acid (c)

Methyl 3-(4-hydroxyphenyl)-2-methoxypropanoate (132 g, 0.631 mol) wasdissolved in methanol (700 mL) and 5N sodium hydroxide (631 mL, 3.16mol) was added dropwise at ambient temperature. The solution was stirredfor 16 hours at ambient temperature. The methanol was removed undervacuum, and water (500 mL) was added. The mixture was extracted withMTBE (2×500 mL). The aqueous solution was brought to pH=1 withconcentrated HCl and then extracted with MTBE (2×500 mL). The organicextracts were dried (MgSO₄), filtered, and concentrated under vacuum togive the racemic acid as an oil (110 g) which was crystallized uponstanding. ¹H-NMR (DMSO): 7.0 (d, 2H); 6.6 (d, 2H); 4.0 (m, 1H); 2.8 (m,2H). MS (ES)=195.1 (M−1).

Step 2: (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid (d)

Cinchonidine salt of (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid.

A slurry consisting of 3-(4-hydroxyphenyl)-2-methoxypropanoic acid(21.21 g, 0.1081 mol), (−)-cinchonidine (31.83 g, 0.1081 mol), and THF(424 mL) was heated briefly at reflux to give a red-brown solution. Themixture was cooled to ambient temperature and stirred for 3 days. Theresulting-slurry was cooled to 0° C. for 4 hours and filtered to giveabout 17.06 g of the cinchonidine salt (71.2% ee by chiral HPLC). Thecinchonidine salt was slurried in THF, heated to reflux for 1 hour, andcooled to ambient temperature overnight. The mixture was cooled to 0° C.for 2 hours and filtered to give about 14.87 g of the cinchonidine salt(83.0% ee by chiral HPLC). The cinchonidine salt was slurried again inTHF, and heated to reflux for 1 hour, and cooled to ambient temperature.The mixture was cooled to 0° C. for 2 hours and filtered to give about12.87 g (24%) of the cinchonidine salt of(2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid (91.4% ee by chiralHPLC).

(2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid

The cinchonidine salt of (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoicacid (73.59 g, 0.15 mol) (98.1% ee by chiral HPLC) was suspended in 1NHCl solution (750 mL) and extracted with methyl tert butyl ether (3×200mL). The combined extracts were dried (Na₂SO₄) and concentrated to giveabout 24.12 g (82%) of (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid(96.7% ee by chiral HPLC). ¹H NMR (DMSO-d₆): δ 2.72–2.89 (m, 2H), 3.21(s, 3H), 3.8–3.87 (m, 1H), 6.64–6.67 (d, 2H), 6.97–7.02 (d, 2H), 9.15(s, broad, 1H), 12.62 (s, broad, 1H). MS (ES⁺): m/z 219.0 ([M+Na]⁺). MS(ES⁻) m/z 195.1 ([M−H]⁻). [α]_(D)=−2.2° (c=1, MeOH).

Step 3: ethyl (2S)-2-methoxy-3-(4-hydroxyphenyl)propanoate (e)

A solution of (2S)-3-(4-hydroxyphenyl)-2-methoxypropanoic acid (35 g) in140 ml of ethanol was mixed with 5.66 ml of concentrated sulfuric acidand stirred at room temperature until complete as indicated by HPLC. Theethanol was removed via vacuum distillation (55° C./28″Hg) and 110 ml ofwater was added. The pH was adjusted to about 7 to 8 with sodiumbicarbonate, and the mixture was extracted with add 50 ml ethyl acetate(3×50 ml). The organic layers were combined, washed with 50 ml 20% NaClsolution, dried with 15 g of magnesium sulfate, and concentrate productto afford ethyl (2S)-2-methoxy-3-(4-hydorxyphenyl)propanoate as an oil.¹H-NMR (CDCl₃): 7.1 (d, 2H); 6.7(d, 2H); 4.2(m, 2H); 3.9(m, 1H); 3.6(s,3H); 2.95(m, 2H); 1.25(t, 3H). MS (ES): 223.2 (M−1).

Example 247 Synthesis of(2S)-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoic acid

Step 1: 1-bromo-3-(4-phenoxyphenyl)propane (a)

To a 22 L flask was added 4-phenoxyphenol (900 g), 1,3-dibrompropane(5858 g), powered potassium carbonate (1335 g), and methyl ethyl ketone(9 L). The mixture was stirred for 30 minutes at 22° C. The off-whiteslurry was heated to a gentle reflux (˜83° C.) and held at thattemperature for 16 hours. The off white slurry was cooled to 25° C. andvacuum filtered, washing the cake of inorganic salts with methyl ethylketone (4 L). The filtrate was concentrated on a rotary evaporator whileincreasing the temperature to 90° C. under house vacuum. After thecondensation had stopped, the oil was held at 90° C. under vacuum for anadditional two hours to ensure the remaining 1,3-dibrompropane below 8%by GC analysis. The residue was dissolved in 3 L of methyl alcohol, andthe white slurry was cooled slowly to about 0–5° C. and held at thattemperature overnight. The product was filtered, washed with cold methylalcohol (6 L), and dried at 30° C. for about 20 hours to afford about1234 g of compound (a) in 84% yield (99.4% pure by GC). ¹H-NMR (CDCl₃):7.3(2H, m), 7.1(2H, m), 7.0(2H, m), 6.9(2H, m), 4.1(2H, m); 3.6(2H, m);2.3(2H, m).

Step 2: ethyl(2S)-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoate (b)

1-Bromo-3-(4-phenoxyphenyl)propane (1337 g), ethyl(2S)-2-methoxy-3-(4-hydorxyphenyl)propanoate (957 g) anddimethylformamide (5 L) were charged to a 22 L flask. After a solutionwas obtained, powered-potassium carbonate (1770 g) was added. Themixture was stirred for 16 hours at ambient temperature and thenquenched by adding water (6.5 L) while maintaining temperature at 20 to30° C. The aqueous layer was extracted three times with ethyl acetate (5L each). The combined organic layers were washed with water (3×4 L) andbrine (4 L). The organic layer was then dried with sodium sulfate (1000g), filtered, and washed with ethyl acetate. The filtrate wasconcentrated to afford about 1974 g of crude (b). ¹H-NMR (CDCl₃): 7.3(m,2H); 7.2(d, 2H); 7.0(m, 1H); 6.95(m,4H); 6.9(d, 2H); 6.85(d, 2H); 4.2(m,2H); 4.15(m, 4H); 3.9(t, 1H); 3.39(s, 3H); 2.99(m, 2H); 2.25(m, 2H);1.25(m, 3H). MS (ES)=468.2 (M+NH₄).

Step 3:2S-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]phenyl}propanoic acid,sodium salt (c)

To a 22 L flask, a solution of compound (b) (987 g) in ethanol (10 L)was added and stirred, followed by adding 5 N NaOH (4.4 L) for over 60minutes at a temperature at 20 to 30° C. The slurry was stirred forabout an hour at ambient temperature and then cooled to 10–15° C. wherethe mixture was held at that temperature for 1 hour and filtered. Thesolid was washed with alcohol (8 L) and MTBE (50 L) to afford thecompound (c), which can be further purified by recrystallizing fromethyl acetate: ¹H-NMR (DMSO): 7.35(m, 2H); 7.1(m, 3H); 7.0(m, 4H),6.9(d, 2H); 6.8(d, 2H); 4.1(m, 4H); 3.4(t, 1H); 3.1(s, 3H); 2.8(dd, 1H);2.6(m, 1H); 2.15(m, 2H). MS (ES): 421.2 (M−1).

Step 4:2S-2-methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}propanoic acid(d)

2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acidethyl ester (b) (12.15 g, 27 mmol) was dissolved in ethanol (250 ml) atambient temperature, and 5N NaOH (54 ml, 270 mmol) was added dropwise.The slurry was stirred at ambient temperature for 2 hours. The mixturewas diluted with water (250 ml), and conc. HCl (33 ml) was addeddropwise. The resulting slurry was stirred at ambient temperature forabout 2 hours. The white solid was filtered and dried under vacuum at70° C. for 16 hours to afford about 10.5 g of the compound (d). ¹H-NMR(CDCl₃): 7.3 (m, 2H), 7.18 (d, 2H), 7.07 (t, 1H), 6.9 (m, 8H), 4.19 (m,4H), 4.0 (m, 1H), 3.4 (s, 3H), 3.0 (m, 2H), 2.25 (m, 2H). MS (ES): 421.2(M−1).

Example 248

(2S)-(2′RS)-2-Methoxy-{4-[2′-methyl-3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid

A solution of(2S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid {4-[2-methylen-3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid from Example 74, in ethanol was treated with Pd/C and H₂ for over 2hours at 1 atm. The mixture was filtered through celite and concentratedto dryness to afford the title compound as a mixture of isomers. MS (ES)for C₂₆H₂₈O₆ [M+NH₄]⁺: 454.2, [M−H]⁻: 435.2.

Example 249 2(S)-3-[4-(3-Benzyloxy-propoxy)-phenyl]-2-methoxypropionicacid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-phenyl]-2-methoxypropionic acid linked to Wang'sResin (Example 94, Step C) via the Mitsunobu reaction-cleavage (StandardProcedure G). ¹H-NMR (200.15 MHz, CDCl₃): 7.4–7.2 (m, 5H), 7.14 (d, 2H,J=8.6), 6.82 (d, 2H, J=8.6), 4.52 (s, 2H), 4.06 (t, 2H, J=6.2), 3.97(dd, 1H, J=7.2, 4.6), 3.65 (t, 2H, J=6.2), 3.39 (s, 3H), 3.09 (dd, 1H,J=14.4, 4.4), 2.95 (dd, 1H, J=14.4, 7.2), 2.07 (qn, 2H, J=6.2).

Example 250 (2S)-3-[4-(5-Benzyloxy-pentyloxy)-phenyl]-2-methoxypropionicacid

The title compound was prepared from(2S)-3-[4-(3-hydroxy-phenyl]-2-methoxy-propionic acid linked to Wang'sResin (Example 94, Step C) via the Mitsunobu reaction-cleavage (StandardProcedure G) with 5-benzyloxy-pentan-1-ol. ¹H-NMR (200.15 MHz, CDCl₃):7.4–7.3 (m, 5H), 7.14 (d, 2H, J=8.6), 6.81 (d, 2H, J=8.6), 4.51 (s, 2H),4.0–3.9 (m, 3H), 3.50 (t, 2H, J=6.2), 3.39 (s, 3H), 3.08 (dd, 1H,J=14.2, 4.3), 2.95 (dd, 1H, J=14.2, 7.5), 1.9–1.5 (m, 6H).

Example 251(2S)-2-ethoxy-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid

Step A(2S)-2-Hydroxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester

A solution of (2S)-2-hydroxy-3-(4-hydroxy-phenyl)-propionic acid inethanol and H₂SO₄ (catalytic) was stirred overnight. The mixture wasconcentrated to dryness and reconstituted in ethyl acetate. The organiclayer was washed with NaHCO₃, dried over MgSO₄ and concentrated todryness to give the title product. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.03(d, 2H, J=8.6), 7.00 (d, 2H, J=8.7), 6.72–6.77 (m, 1H), 4.44–4.30 (m,1H), 4.22 (q, 2H, J=7.9), 3.13–2–77 (m, 2H), 1.24 (t, 3H, J=7.9).

Step B

(2S)-2-Hydroxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid ethyl ester

To a solution of compound (Step A) in DMF, CsCO₃ (1.0 eq) and4-(3-bromopropoxy)-1-phenoxybenzene (1.1 eq) (Example 244, Step A) wereadded. The mixture was stirred at room temperature overnight. Thesolvent was concentrated in vacuum and ethyl acetate was added. Theorganic layer was washed with water and concentrated to affrod, afterchromatography on silica gel, the title compound. ¹H-NMR (CDCl₃, 200.15MHz): δ 7.28 (dd, 2H, J=8.3, 0.8), 7.17–6.84 (m, 11H), 4.44–4.36 (m,1H), 4.28–4.12 (m, 6H), 3.13–2.87 (m, 2H), 2.79–2.76 (m, 1H), 2.32–2.19(m, 2H), 1.29 (t, 3H, J=7.9).

Step C

2-Ethoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acidethyl ester

A solution of(2S)-2-hydroxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid ethyl ester, AgO₂ (1.5 eq) and ethyl iodide (excess) indichloromethane was stirred over 10 days. The crude mixture was filteredthrough celite and concentrated to dryness. The compound was purified bychromatography to give the title product. ¹H-NMR (CDCl₃, 200.15 MHz): δ7.34–7.26 (m, 2H), 7.18–6.82 (m, 11H), 4.18–4.17 (m, 6H), 4.01–3.94 (m,1H), 3.68–3.53 (m, 1H), 3.43–3.28 (m, 1H), 2.96 (d, 2H, J=6.5), 2.25(qn, 2H, J=6.2), 1.20 (dt, 6H, J=12.6, 7.3).

Step D

(2S)-2-ethoxy-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid

The title compound was prepared from2-ethoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acidethyl ester (Step C) by standard hydrolysis procedure C (LiOH). MS (ES)for C₂₆H₂₈O₆ [M+NH₄]⁺: 454.2, [M−H]⁻:435.2.

Example 252(2S)-2-Benzyloxy-3-{4-[3-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared as in Example 251 using benzyl bromideas alkylating agent. Hydrolysis under the Standard Procedure C of thecorresponding ethyl ester derivative gave us the title compound. MS(ES)for C₃₁H₃₀O₆ [M+NH₄]⁺: 516.2, [M−H]⁻: 497.2.

Example 253(2S)-3-{4-[3-(4-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-(4-{3-[4-(4-hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester

Concentrated sulfuric acid (0.05 mL) was added to a solution of(2S)-3-(4-{3-[4-(4-hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid (0.18 mmol, 80 mg) (example 170) in ethanol (20 mL) at roomtemperature. The mixture was stirred at room temperature for three days,and the solvent was concentrated under vacuum. After addition of water,the mixture was neutralized with solid NaHCO₃ and extracted with ethylacetate (3×15 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated under vacuum to afford the title compound.¹H-NMR (200.15 MHz, CDCl₃): δ 7.76 (d, 2H, J=8.6), 7.71 (d, 2H, J=8.8),7.13 (d, 2H, J=8.6), 6.91–6.80 (m, 6H), 6.37 (br s, 1H), 4.25–4.10 (m,6H), 3.93 (dd, 1H, J=7.0, 5.6), 3.35 (s, 3H), 2.95 (m, 2H), 2.27 (qn,2H, J=5.9), 1.23 (t, 3H, J=7.1).

Step B

(2S)-3-{4-[3-(4-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

Diisopropyl azodicarboxilate (0.2 mmol, 0.04 mL) was added dropwise to asolution of 2-(tert-butyl-dimethyl-silanyloxy)-ethanol (0.26 mmol, 46mg) (Example 122, Step A),(2S)-3-(4-{3-[4-(4-hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester (0.13 mmol, 65 mg) and triphenylphosphine (0.2 mmol, 38mg) in anhydrous toluene (2 mL) at 0° C. under nitrogen. The mixture wasstirred overnight at room temperature, quenched with water and extractedwith ethyl acetate (3×15 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated under vacuum. The crude mixturewas chromatographed on silica gel using a 4/1 hexane/EtOAc mixture aseluent to afford the title product ¹H-NMR (200.15 MHz, CDCl₃): δ 7.76(d, 4H, J=8.9), 7.13 (d, 2H, J=8.6), 6.96 (d, 4H, J=8.6), 6.83 (d, 2H,J=8.6), 4.26–4.09 (m, 8H), 4.02–3.87 (m, 3H), 3.35 (s, 3H), 2.97 (m,2H), 2.28 (qn, 2H, J=5.9), 1.23 (t, 3H, J=7.1), 0.91 (s, 9H), 0.11 (s,6H).

Step C

(2S)-3-{4-[3-(4-{4-[2-(tert-Butyldimethyl-silanyloxy)-ethoxy]-benzoyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-{4-[2-tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester by the standard hydrolysis procedure C (LiOH). ¹H-NMR(200.15 MHz, CDCl₃): δ 7.76 (dd, 4H, J=8.6, 1.6), 7.15 (d, 2H, J=8.6),6.95 (dd, 4H, J=8.8, 1.6), 6.83 (d, 2H, 8–0.6), 4.24 (t, 2H, J=6.0),4.17–4.09 (m, 5H), 4.02–3.94 (m, 3H), 3.39 (s, 3H), 3.12–2.90 (m, 2H),2.27 (qn, 2H, J=6.0), 0.91 (s, 9H), 0.11 (s, 6H).

Example 254(2S)-3-[4-(3-{4-[4-(2-Hydroxy-ethoxy)-benzoyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionicacid

The compound of(2S)-3-{4-[3-(4-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid (Example 253, Step C) (0.05 mmol, 30 mg) was dissolved in 5 mL of amixture of acetic acid, THF and H₂O (3:1:1) and stirred at roomtemperature for 2 hours. The mixture was diluted with H₂O and extractedwith ethyl acetate (4×20 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated under vacuum to afford the titlecompound. MS(ES) for C₂₈H₃₀O₈ [M+H]⁺: 495.1

Example 255(2S)-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propionicacid

Step A3-(4-Benzyloxy-phenyl-2-hydroxy-propionic acid ethyl ester

A mixture of 2-hydroxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester(Example 251, Step A) (5.2 mmol, 1.1 g), benzyl bromide (5.2 mmol, 0.62mL) and potassium carbonate (15.7 mmol, 2.2 g) in acetonitrile (20 mL)was refluxed overnight. The mixture was cooled down to room temperatureand concentrated to dryness to give a crude, which was purified bycolumn chromatography on, silica gel to afford the title product.

MS (ES) for C₁₈H₂₀O₄ [M+NH₄]⁺: 318.3

Step B

(2S)-2-Allyloxy-3-(4-benzyloxy-phenyl)-propionic acid ethyl ester

Silver (I) oxide (5.7 mmol, 1.3 g) was added to a mixture of(S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid ethyl ester (3.8mmol, 1.2 g) and alkyl bromide (19 mmol, 1.6 mL) in DMF (10 mL) at roomtemperature, and the reaction mixture was heated at 50° C. for 20 hours.After cooling to room temperature, the mixture was diluted with H₂O andextracted with ethyl acetate (5×25 mL). The combined organic layers werewashed with water (4×20 mL) and brine; dried over MgSO₄, filtered andconcentrated under vacuum. The crude mixture was chromatographed onsilica gel using a 4/1 hexane/ethyl acetate mixture as eluent to affordthe title product. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.46–7.32 (m, 5H), 7.18(d, 2H, J=8.9), 6.91 (d, 2H, J=8.9), 5.91–5.72 (m, 1H), 5.25–5.12 (m,2H), 5.05 (s, 2H), 4.11–4.03 (4H, m), 3.94–3.84 (m, 1H), 2.99 (d, 2H,J=7.0), 1.23 (t, 3H, J=7.0).

Step C

(2S)-3-(4-Hydroxy-phenyl)-2-propoxy-propionic acid ethyl ester

A mixture of (S)-2-allyloxy-3-(4-benzyloxy-phenyl)-propionic acid ethylester (1.33 mmol, 450 mg) and 10% Pd/C (45 mg) in EtOH (15 mL) werestirred under hydrogen atmosphere (1 atm) for 18 hours. The mixture wasfiltered through celite and concentrated under vacuum to afford thetitle product. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.10 (d, 4H, J=8.6), 6.73(d, 2H, J=8.4), 5.90 (brs, 1H), 4.16 (q, 2H, J=7.3), 3.94 (t, 1H,J=6.7), 3.53–3.45 (m, 1H), 3.27–3.16 (m, 1H), 2.93 (d, 2H, J=6.5), 1.54(m, 2H), 1.22 (t, 3H, J=7.3), 0.84 (t, 3H, J=7.5).

Step D

(2S)-3-{4-[3-(4-Phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propionicacid ethyl ester

The title compound was prepared from(S)-3-(4-hydroxy-phenyl)-2-propoxy-propionic acid ethyl ester and3-(4-phenoxy-phenoxy)-propyl bromide (Example 244) using the StandardProcedure L. The product was purified by column chromatography on silicagel using 9/1 Hexan/Ethyl acetate mixture as eluent to afford the titleproduct. MS(ES) for C₂₉H₃₄O₆ [M+NH₄]⁺: 496.3

Step E

(2S)-3-{4-[3-(4-Phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propionicacid

The title compound was prepared from(S)-3-{4-[3-(4-Phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propionicacid ethyl ester by the standard hydrolysis procedure C (LiOH). MS(ES)for C₂₇H₃₀O₆ [M−H]⁻: 449.2

Example 256 (2S)-3-{4-[3-(4-Benzoylphenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acid

Step A(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionicacid methyl ester

The title compound was prepared from2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid methyl ester and[4-(3-bromo-propoxy)-phenyl]-phenyl-methanone (prepared from4-hydroxybenzophenone following the same procedure as in (Example 132,Steps B to D) using the Standard Procedure I. The product was purifiedby column chromatography on silica gel using a hexane/ethyl acetatemixture (4/1) as eluent to give the racemic product. This racemicmixture was subjected to chiral HPLC separation to give the pureenantiomer. ¹H-NMR (200.15 MHz, CDCl₃): δ 7.83–7.72 (m, 4H), 7.57–7.42(m, 3H), 7.14 (d, 2H, J=8.8), 6.96 (d, 2H, J=8.8), 6.83 (d, 2H, J=8.6),4.25 (t, 2H, J=6.1), 4.15 (t, 2H, J=6.2), 3.98 (dd, 1H, J=7.1, 6.0),3.70 (s, 3H), 3.58 (dd, 1H, J=9.1, 7.0), 3.33 (dd, 1H, J=9.1, 7.0), 2.94(m, 2H), 2.28 (qn, 2H, J=6.2), 1.25 (t, 3H, J=7.3).

Step B

(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acidmethyl ester by the standard hydrolysis procedure C (LiOH). MS(ES) forC₂₇H₂₈O₆ [M−H]⁻: 447.1

Example 257(2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acid

Step A(2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acidethyl ester

The title compound was prepared from(S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester and3-(4-benzyl-phenoxy)-propyl bromide (prepared from 4-benzylphenolfollowing the same procedure as in (Example 132, Steps B to D) using theStandard Procedure I. The product was purified by column chromatographyon silica gel using a hex ae/ethyl acetate mixture (4/1) as eluent togive the title product. MS(ES) for C₂₉H₃₄O₅ [M+NH₄]⁺: 480.2.

Step B

(2S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acid

The title compound was prepared from(S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acidethyl ester by the standard hydrolysis procedure C (LiOH). MS(ES) forC₂₇H₃₀O₅ [M−H]⁻: 433.1

Example 258(2S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-ethoxy-propionicacid

Step A(2S)-3-(3-Chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid ethyl ester

N-Chlorosuccinimide (2.1 mmol) was added to a solution of(S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.1 mmol)in acetonitrile (12 mL) at room temperature, and the mixture was stirredat the same temperature for 5 days. Solvent was evaporated under vacuum,and the residue was washed with CCl₄. The resulting suspension wasfiltered, and the filtrate was concentrated under vacuum andchromatographed on silica gel using a 9/1 hexane/EtOAc mixture as eluentto afford title product. MS(ES) for C₁₃H₁₇ClO₄ [M−H]⁻: 271.0

Step B

(2S)-3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-ethoxy-propionicacid ethyl ester

The title compound was prepared from(S)-2-ethoxy-3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl esterand [4-(3-bromo-propoxy)-phenyl]-phenyl-methanone (Example 256) usingthe Standard Procedure I. The product was purified by columnchromatography on silica gel using a 4/1 Hexane/Ethyl acetate mixture aseluent to give the title product. MS(ES) for C₂₉H₃₁ClO₆ [M+H]⁺: 511.1

Step C

(2S)-3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from(S)-3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-ethoxy-propionicacid methyl ester by the standard hydrolysis procedure C (LiOH). ¹H-NMR(200.15 MHz, CDCl₃): δ 7.82–7.72 (m, 4H), 7.56–7.43 (m, 3H), 7.07 (dd,1H, J=8.8, 2.0), 6.97 (d, 2H, J=8.9), 6.86 (d, 2H, J=8.3), 4.31 (t, 2H,J=6.0), 4.21 (t, 2H, J=6.0), 4.10–4.02 (m, 1H), 3.66–3.44 (m, 2H),3.10–2.87 (m, 2H), 2.33 (qn, 2H, J=6.2), 1.20 (t, 3H, J=7.0).

Example 259(2S)-4′-{3-[4-(2-Carboxy-2-methoxy-ethyl)-2-methoxy-phenoxy]-propoxy}-biphenyl-4-carboxylicacid

Step A3-[4-(3-Hydroxy-propoxy)-3-methoxy-phenyl]-2-methoxypropionic acidmethyl ester

A mixture of 3-(4-Hydroxy-3-methoxy-phenyl)-2-methoxypropionic acidmethyl ester (Example 130, Step B) and3-(tert-butyl-dimethyl-silanyloxy)-propan-1-ol were treated underMitsunobu standard conditions B using DIAD and toluene. The productobtained was treated under Standard Procedure E for cleavage protectedalcohols to give the title product. The 2S isomer was separated from the2R isomer by chiral. ¹H-NMR (CDCl₃, 200.15 MHz): δ 6.84–6.72 (m, 3H),4.17 (t, 2H, J=5.9), 3.94 (dd, 2H, J=7.0, 5.4), 3.87 (t, 2H, J=5.4),3.84 (s, 3H), 3.73 (s, 3H), 3.35 (s, 3H), 2.97–2.93 (m, 2H), 2.11–2.00(m, 2H).

Step B

(2S)-4′-{3-[2-Methoxy-4-(2-methoxy-2-methoxycarbonyl-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylicacid methyl ester

3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid methylester (Step A) and 4′-hydroxy-biphenyl-4-carboxylic acid methyl ester(Example 197, Step A) were treated under Mitsunobu standard condition B.The crude was purified by chromatography on silica gel (hexanes/ethylacetate 7:3) to afford the title compound.

¹H-NMR (CDCl₃, 200.15 MHz): δ 8.07 (d, 2H, J=8.6), 7.58 (dd, 4H, J=10.8,8.9), 7.14 (d, 2H, J=8.9), 6.99 (d, 2H, J=8.9), 6.84 (d, 2H, J=8.6),4.24–4.12 (m, 6H), 3.94–3.90 (m, 4H), 3.35 (s, 3H), 2.97–2.94 (m, 2H),2.27 (qn, 2H, J=5.9), 1.23 (t, 3H, J=7.0).

Step C

(2S)-4′-{3-[4-(2-Carboxy-2-methoxy-ethyl)-2-methoxy-phenoxy]-propoxy}-biphenyl-4-carboxylicacid

The title compound was prepared from4′-{3-[2-methoxy-4-(2-methoxy-2-methoxycarbonyl-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylicacid methyl ester (Step B) by standard hydrolysis procedure C (NaOH).¹H-NMR (MeOD, 300.15 MHz):

δ 8.07 (d, 2H, J=8.5), 7.69 (d, 2H, J=8.5), 7.63 (d, 2H, J=8.7), 7.06(d, 2H, J=8.7), 6.91–6.88 (m, 2H), 6.78 (dd, 1H, J=8.1, 1.6), 4.25 (t,2H, J=6.3), 4.18 (t, 2H, J=6.0), 3.94 (dd, 1H, J=7.9, 4.4), 3.82 (s,3H), 3.33 (s, 3H), 3.01 (dd, 1H, J=14.1, 4.4), 2.88 (dd, 1H, J=13.9,7.7), 2.26 (qn, 2H, J=6.0).

Example 260(2S)-3-{4-[3-(4′-tert-Butyl-biphenyl-4-yloxy)-propoxy]-2-methoxy-propionicacid

Step A3-Bromopropan-1-ol

To a solution of 1,3-propanediol (5 g, 66 mmol) and benzene (132 mL) wasadded hydrobromic acid 48% (8 mL). The resulting mixture was heated atreflux for 20 hours while trapping the water formed using a Dean-Starkwater separator. The mixture was washed with 2N NaOH solution, 5% HCl,water and brine. The organic layer was dried (Na₂SO₄) and evaporatedunder reduced pressure. ¹H-NMR (CDCl₃, 300.15 MHz): δ 3.78 (2H, t,J=6.0), 3.52 (2H, t, J=6.0), 2.07 (2H, m).

Step B

3-[4-(3-Bromo-propoxy)-2-methoxy-phenyl]-2-methoxy-propionic acid methylester

3-(4-Hydroxy-2-methoxy-phenyl)-2-methoxy-propionic acid methyl ester(Example 188, Step C) and 3-bromo-propan-1-ol (Step A) were treated inthe standard Mitsunobu conditions B (DIAD/toluene) to afford the titlecompound. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.01 (d, 1H, J=8.3), 6.39 (m,2H), 4.06 (t, 2H, J=5.9), 4.00–3.96 (m, 1H), 3.78 (s, 3H), 3.67 (s, 3H),3.57 (t, 2H, J=6.4), 3.31 (s, 3H), 2.99 (dd, 1H, J=13.7, 6.2), 2.91 (dd,1H, J=13.7, 7.5), 2.34–2.22 (m, 2H).

Step C

(2S)-3-{4-[3-(4′-tert-Butyl-biphenyl-4-yloxy)-propoxy-2-methoxy-phenyl]-2-methoxy-propionicacid methyl ester

3-[4-(3-Bromo-propoxy)-2-methoxy-phenyl]-2-methoxy-propionic acid methylester (Step B) and 4′-tert-butyl-biphenyl-4-ol (Example 221, Step A)were treated under Standard Procedure K. The enantiomers were separatedby chiral HPLC. The (2S) isomer was separated from the 2R isomer bychiral HPLC (Chiralpack AD, Hexane 0.05% TFA/IPA, 75/25, isocratic mode,1 mL/min; RT=7.70 min). ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.53–7.41 (m, 6H),7.05–6.95 (m, 3H), 6.45–6.40 (m, 2H), 4.21 (d, 2H, J=6.2), 4.14 (d, 2H,J=6.2), 4.05–3.98 (m, 1H), 3.80 (s, 3H), 3.69 (s, 3H), 3.33 (s, 3H),3.01 (dd, 1H, J=13.4, 6.2), 2.92 (dd, 1H, J=13.4, 7.5), 2.27 (qn, 2H,J=6.2).

Step D

(2S)-3-{4-[3-(4′-tert-Butyl-biphenyl-4-yloxy)-propoxy]-2-methoxy-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4′-tert-butyl-biphenyl-4-yloxy)-propoxy]2-methoxy-phenyl}-2-2-methoxy-propionicacid methyl ester (Step C) by standard hydrolysis procedure C (NaOH).¹H-NMR (Acetone-d₆, 300.15 MHz): δ 7.57 (d, 2H, J=8.7), 7.53 (d, 2H,J=8.7), 7.45 (d, 2H, J=8.5), 7.06–7.02 (m, 3H), 6.55 (d, 1H, J=2.0),6.46 (dd, 1H, J=8.3, 2.2), 4.26–4.17 (m, 4H), 3.96 (dd, 1H, J=7.9, 5.7),3.81 (s, 3H), 3.26 (s, 3H), 2.25 (qn, 2H, J=6.3), 1.33 (s, 9H).

Example 261(2S)-3-(4-{3-[4-(4-Hydroxy-phenoxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step A(2S)-3-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

A mixture of (2S)-3-(4-hydroxy-phenyl)-2-methoxy propionic acid ethylester and 3-(tert-Butyl-dimethyl-silanyloxy)-propan-1-ol were treatedunder Mitsounobu coupling standard conditions B using DIAD and toluene.

Step B

(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid ethylester

A solution of(2S)-3-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester was treated under Standard Procedure E for cleaveageprotected alcohols to give the title product.

Step C

3-(4-{3-[4′-(tert-Butyl-dimethyl-silanyloxy)-biphenyl-4-yloxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester

(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl)-2-methoxy-propionic acid ethylester and 4′-(tert-butyl-dimethyl-silanyloxy)-biphenyl-4-ol (Example196, Step A) were treated under Mitsunobu procedure B (DIAD, toluene),to afford the title compound.

Step D

(2S)-3-(4-{3-[4-(4-Hydroxy-propoxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from3-(4-{3-[4′-(tert-butyl-dimethyl-silanyloxy)-biphenyl-4-yloxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester (Step A) by standard hydrolysis procedure C (NaOH).¹H-NMR (CDCl₃, 200.15 MHz): δ 7.15 (d, 2H, J=8.6), 6.92–6.74 (m, 10H),4.15–4.09 (m, 4H), 3.98 (dd, 1H, J=7.3, 4.6), 3.39 (s, 3H), 3.09 (dd,1H, J=14.2, 4.6), 2.95 (dd, 1H, J=14.2, 7.3), 2.23 (qn, 2H, J=5.9).

Example 262(2S)-2-Methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-propoxy}-phenyl)-propionicacid

Step A4-(2,2,3,3-tetrafluoro-propoxy)-1-benzyloxy-phenol

To a solution of methanesulfonic acid 2,2,3,3-tetrafluoropropyl ester(obtained from 2,2,3,3-tetrafluoropropanol and methanesulfonyl chlorideas described in (Example 268, Step A) (0.35 mmol, 74 mg) and4-benzyloxy-phenol (0.175 mmol, 35 mg) in DMF (1 mL) was added K₂CO₃,and the was stirred at 100° C. for 20 hours. Waiter: was added and theaqueous layer was extracted twice with hexane and once with ethylacetate. The combined organic layers were dried (Na₂SO₄), filtered andevaporated. The crude was purified by chromatography on silica gel(hexane/ethyl acetate 4:1) to afford the title compound. ¹H-NMR (CDCl₃,200.15 MHz): δ 7.42–7.32 (m, 5H, 6.96–6.84 (m, 4H), 6.06 (tt, 1H,J=53.0, 5.1), 5.03 (s, 2H), 4.29 (dt, J=12.0, 1.6).

Step B

4-(2,2,3,3-Tetrafluoro-propoxy)-phenol

4-(2,2,3,3-tetrafluoro-propoxy)-benzyloxy-phenol (0.09 mmol, 28 mg)(Step A) was dissolved in MeOH (2 mL) and Pd(C) (40% weight, 10 mg) wasadded. The mixture was stirred for 90 minutes under H₂ atmosphere (1atm), and filtered through a celite pad (EtOH). The filtrate wasconcentrated to give the title compound. ¹H-NMR (CDCl₃, 200.15 MHz): δ6.85–6.75 (m, 4H), 6.05 (dt, J=53.2, 4.8), 4.28 (dt, 2H, J=12.1, 1.6).

Step C

(2S)-2-Methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-propoxy}-phenyl)-propionicacid ethyl ester

3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 173, Step A) and 4-(2,2,3,3-tetrafluoro-propoxy)-phenol (StepB) were treated under ester K to afford the title compound ¹H-NMR(CDCl₃, 200.15 MHz): δ 7.13 (d, 2H, J=8.6), 6.85–6.80 (m, 6H), 6.05 (dt,1H, J=53.2, 5.1), 4.22–4.08 (m, 8H), 3.90 (dd, 1H, J=7.0, 5.6), 3.35 (s,3H), 3.04–2.86 (m, 2H), 2.22 (qn, 2H, J=6.2).

Step D

(2S)-2-Methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-propoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-2-methoxy-3-(4-{3-[4-(2,2,3,3-tetrafluoro-propoxy)-phenoxy]-propoxy}-phenyl)-propionicacid ethyl ester (Step C) by standard hydrolysis procedure C (NaOH).¹H-NMR (CDCl₃, 200.15 MHz): δ 7.14 (d, 2H, J=8.6), 6.84–6.79 (m, 6H),6.04 (tt, 1H, J=53.0, 4.8), 4.27 (t, 2H, J=12.0), 4.09 (t, 4H, J=5.9),3.97–3.91 (m, 1H), 3.34 (s, 3H), 3.11–2.87 (m, 2H), 2.20 (qn, 2H,J=5.9).

Example 263(2S)-2-Methoxy-3-(4-{3-[4-(3-methyl-butoxy)-phenoxy]-propoxy}-phenyl)-propionicacid

Step A2S)-3-{4-[3-(4-benzyloxy-phenoxy]-phenoxy}-phenyl)-2-methoxy propionicacid ethyl ester

3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid methylester (Example 175, Step B) and 4-benzyloxy-phenol were treated underMitsunobu standard conditions B to afford the title compound. ¹H-NMR(CDCl₃, 200.15 MHz): δ 7.44–7.30 (m, 5H), 7.13 (d, 2H, J=8.6), 6.93–6.73(m, 6H), 5.01 (s, 2H), 4.20–4.06 (m, 6H), 3.90 (dd, 1H, J=7.0, 5.6),3.35 (s, 3H), 3.00–2.93 (m, 2H), 2.22 (qn, 2H, J=6.2), 1.23 (t, 3H,J=7.2).

Step B

(2S)-3-{4-[3-(4-Hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

The title compound was obtained following the hydrogenation procedure(Example 261, Step B), starting from(2S)-3-{4-[3-(4-benzyloxy-phenoxy]-propoxy}-phenyl)-2-methoxy propionicacid ethyl ester. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.13 (d, 2H, J=8.9),6.84–6.71 (m, 6H), 4.23–4.06 (m, 6H), 3.91 (dd, 1H, J=7.3, 5.9), 3.35(s, 3H), 2.97–2.93 (m, 2H), 2.21 (qn, 2H, J=6.2), 1.23 (t, 3H, J=7.3).

Step C

(2S)-2-Methoxy-3-(4-{3-[3-methyl-butoxy)-phenoxy]-propoxy}-phenyl)-propionicacid ethyl ester

(2S)-3-{4-[3-(4-Hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (Step A) was reacted under Mitsunobu procedure B (DIAD,toluene) with 3-methyl-butanol to afford the title compound. ¹H-NMR(CDCl₃, 200.15 MHz): δ 7.13 (d, 2H, J=8.6), 6.85–6.81 (m, 6H), 4.18 (q,4H, J=7.0), 4.08 (d, 2H, J=5.9), 3.96–3.87 (m, 3H), 3.35 (s, 3H),2.97–2.93 (m, 2H), 2.22 (qn, 2H, J=6.2), 1.86–1.60 (m, 3H), 1.23 (t, 5H,J=7.0), 0.95 (d, 6H, J=6.4).

Step D

(2S)-2-Methoxy-3-(4-{3-[3-methyl-butoxy)-phenoxy]-propoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-2-methoxy-3-(4-{3-[4-(3-methyl-butoxy)-phenoxy]-propoxy}-phenyl)-propionicacid ethyl ester (Step B) by standard hydrolysis procedure C (NaOH).¹H-NMR (CDCl₃, 200.15 MHz): δ 7.12 (d, 2H, J=8.4), 6.84–6.80 (m, 6H),4.09 (q, 4H, J=6.2), 3.99–3.88 (m, 3H), 3.37 (s, 3H), 3.07 (dd, 1H,J=14.3, 4.4), 2.93 (dd, 1H, J=14.3, 7.0), 2.19 (qn, 2H, J=6.2),1.90–1.71 (m, 1H), 1.62 (q, 2H, J=6.9), 0.93 (d, 6H, J=6.6).

Example 264(2S)-3-{4-[3-(4-Isobutoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

(2S)-3-{4-[3-(4-Hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (Example 263, Step B) was coupled under the ester Jwith 1-bromo-2-methylpropane to afford the title compound. ¹H-NMR(CDCl₃, 200.15 MHz): δ 7.14 (d, 2H, J=8.6), 6.86–6.82 (m, 6H), 4.11 (q,4H, J=6.2), 3.98 (dd, 1H, J=7.3, 4.6), 3.66 (d, 2H, J=6.5), 3.40 (s,3H), 3.10 (dd, 1H, J=14.5, 4.6), 2.95 (dd, 1H, J=14.5, 7.3), 2.21 (qn,2H, J=6.2), 2.11–1.98 (m, 1H), 1.01 (d, 6H, J=6.7).

Example 265(2S)-3-{4-[3-(4-Isopropoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (Example 263, Step B) and 2-bromopropene following theprocedure described for Example 264. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.14(d, 2H, J=8.3), 6.86–6.82 (m, 6H), 4.40 (qn, 1H, J=5.9), 4.11 (q, 4H,J=5.9), 3.98 (dd, 1H, J=7.3, 4.6), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.2,4.3), 3.01–2.90 (dd, 1H, J=14.2, 7.2), 2.22 (qn, 2H, J=5.9), 1.30 (d,6H, J=6.2).

Example 266(2S)-3-{4-[3-(4-Cyclohexylmethoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (Example 263, Step B) and (bromomethyl)cyclohexanefollowing the procedure described for Example 264.

¹H-NMR (CDCl₃, 200.15 MHz): δ 7.14 (d, 2H, J=8.6), 6.86–6.81 (m, 6H),4.11 (q, 4H, J=6.2), 3.99 (dd, 1H, J=7.3, 4.6), 3.70 (d, 2H, J=6.2),3.40 (s, 3H), 3.10 (dd, 1H, J=14.5, 4.6), 2.96 (dd, 1H, J=14.2, 7.3),2.23 (qn, 2H, J=6.2), 1.88–1.67 (m, 6H), 1.39–0.94 (m, 5H).

Example 267(2S)-2-Methoxy-3-{4-[3-(4-phenetyloxy-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (Example 263, Step B) and (1-bromoethyl)benzenefollowing the procedure described for Example 264. ¹H-NMR (CDCl₃; 300.15MHz): δ 7.32–7.26 (m, 5H), 7.14 (d, 2H, J=8.5), 6.86–6.82 (m, 6H),4.15–4.08 (m, 6H), 4.00 (dd, 1H, J=6.9, 4.4), 3.41 (s, 3H), 3.14–3.05(m, 3H), 2.97 (dd, 1H, J=14.5, 6.9), 2.22 (qn, 2H, J=6.1).

Example 268(2S)-3-(4-{3-[4-(3-Dimethylamino-propoxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step AMethanesulfonic acid 3-dimethylamino-propyl ester

3-Dimethylamino-1-propanol (0.98 mmol, 0.12 mL) was dissolved in THF (2mL). Triethylamine (1.47 mmol, 0.20 mL) was added, and the mixture wascooled at 0° C. Methanesulfonyl chloride (1.08 mmol, 0.08 mL). Was addedand the bath removed. The mixture was warmed to room temperature andstirred for 2 hours. Hexanes were added and the precipitates wereremoved by filtration through celite (hexanes). The filtrate wasconcentrated to afford the title compound. ¹H-NMR (CDCl₃, 200.15 MHz): δ4.29 (t, 2H, J=6.4), 3.00 (s, 3H), 2.39 (t, 2H, J=7.0), 2.22 (s, 6H),1.90 (qn, 2H, J=6.7).

Step B

(2S)-3-(4-{3-[4-(3-Dimethylamino-propoxy)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (Example 263, Step B) and methanesulfonic acid3-dimethylaminopropyl ester (Step A) following the procedure describedfor Example 264. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.14 (d, 2H, J=7.8),6.83–6.77 (m, 6H), 4.10–4.04 (m, 5H), 3.95–3.89 (m, 4H), 3.37 (s, 3H),3.16–3.13 (m, 2H), 3.06–2.99 (m, 2H), 2.77 (s, 6H), 2.21–2.15 (m, 4H).

Example 269(2S)-3-{4-[3-(4-Carboxymethoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step AMethanesulfonyloxy-acetic acid ethyl ester

The title compound was prepared following the procedure described formethanesulfonic acid 3-dimethylamino-propyl ester (Example 268, Step A)starting from ethyl glycolate. ¹H-NMR (CDCl₃, 200.15 MHz): δ 4.75 (s,2H), 4.27 (q, 2H, J=7.3), 3.20 (s, 3H), 1.31 (t, 3H, J=7.3).

Step B

(2S)-3-{4-[3-(4-Carbomethoxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (Example 263, Step B) and methane-sulfonyloxy-aceticacid ethyl ester (Step A) by following the procedure described forExample 264. ¹H-NMR (MeOD, 200.15 MHz): δ 7.13 (d, 2H, J=8.6), 6.86–6.81(m, 6H), 4.57 (s, 2H), 4.15–4.06 (m, 4H), 3.91 (dd, 1H, J=7.8, 4.8),3.31 (s, 3H), 2.99 (dd, 1H, J=14.2, 4.6), 2.85 (dd, 1H, J=14.2, 7.5),2.17 (qn, 2H, J=6.2).

Example 270(2S)-3-(4-{3-[4-(1H-Indol-5-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

Step A(2S)-3-{4-[3-(4-Iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acidethyl ester

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterExample 173, Step A) and 4-iodo-phenol were treated under ester K(Cs₂CO₃) to afford the title compound. ¹H-NMR (CDCl₃, 200.15 MHz): δ7.54 (d, 2H, J=8.9), 7.13 (d, 2H, J=8.6), 6.82 (d, 2H, J=8.9), 6.68 (d,2H, J=9.1), 4.23–4.08 (m, 6H), 3.90 (dd, 1H, J=7.3, 5.9), 3.35 (s, 3H),2.97–2.93 (m, 2H), 2.23 (qn, 2H, J=6.2), 1.23 (t, 3H, J=7.0).

Step B

(2S)-3-(4-{3-[4-(1H-Indol-5-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester

To a stirred mixture of(2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acidethyl ester (0.10 mmol, 50 mg) (Step A), 5-indolyl-boronic acid (0.114mmol, 18 mg) and powered cesium carbonate (0.23 mmol, 35 mg) in DME (0.5mL) was added Pd(PPh₃)₄ (0.003 mmol, 4 mg). The mixture was flushed withnitrogen and maintained under nitrogen while being heated at reflux in a100° C. oil bath. The mixture was stirred for 6 hours, and then cooledto room temperature and diluted with ethyl acetate and water. Theorganic layer was dried (Na₂SO₄) and concentrated. The crude product waspurified by chromatography on silica gel (CH₂Cl₂/EtOAc 96:4) to affordthe title compound ¹H-NMR (CDCl₃, 200.15 MHz): δ 8.20 (broad s, 1H),7.80 (d, 1H, J=0.8), 7.56 (d, 3H, J=8.9), 7.41 (d, 2H, J=1.6), 7.23 (dd,1H, J=3.2, 2.4), 7.15 (d, 3H, J=8.6), 6.99 (d, 2H, J=8.9), 6.85 (d, 3H,J=8.6), 6.60–6.58 (m, 1H), 4.24–4.11 (m, 8H), 3.92 (dd, 1H, J=7.3, 5.9),3.35 (s, 4H), 2.98–2.94 (m, 3H), 2.28 (qn, 2H, J=5.9), 1.24 (t, 4H,J=7.3).

Step C

(2S)-3-(4-{3-[4-(1H-Indol-5-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

The title compound was obtained from(2S)-3-(4-{3-[4-(1H-indol-5-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid ethyl ester (Step B) by following the standard hydrolysis procedureC (NaOH). ¹H-NMR (CDCl₃, 200.15 MHz): δ 8.17 (broad s, 1H), 7.80 (s,1H), 7.56 (d, 2H, J=8.6), 7.42 (s, 2H), 7.24–7.21 (m, 1H), 7.15 (d, 2H,J=8.6), 6.98 (d, 2H, J=8.6), 6.86 (d, 2H, J=8.6), 6.59—6.59 (m, 1H),4.23–4.13 (m, 4H), 3.98 (dd, 1H, J=7.3, 4.3), 3.39 (s, 3H), 3.10 (dd,1H, J=14.5, 4.0), 2.95 (dd, 1H, J=14.5, 7.3), 2.27 (qn, 2H, J=6.2).

Example 271(2S)-2-Methoxy-3-{4-[3-(4-pyridin-3-yl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acidethyl ester (Example 270, Step A) and 3-pyridyl boronic acid byfollowing the procedure described for Example 270 (Steps B and C).¹H-NMR (MeOD, 300.15 MHz): δ 8.76 (s, 1H), 8.46 (s, 1H), 8.05 (d, 1H,J=8.1), 7.60 (d, 2H, J=8.7), 7.49 (dd, 1H, J=7.7, 4.8), 7.19 (d, 2H,J=8.5), 7.09 (d, 2H, J=8.7), 6.85 (d, 2H, J=8.5), 4.24 (t, 2H, J=6.1),4.17 (t, 2H, J=6.3), 3.74 (dd, 1H, J=8.7, 3.8), 3.27 (s, 3H), 2.97 (dd,1H, J=14.3, 3.8), 2.81 (dd, 1H, J=14.1, 8.5), 2.26 (qn, 2H, J=6.0).

Example 272(2S)-2-Methoxy-3-{4-[3-(4-pyridin-4-yl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acidethyl ester (Example 270, Step A) and 4-pyridyl boronic acid byfollowing the procedure described for Example 270 (Steps B and C).¹H-NMR (CDCl₃, 200.15 MHz): δ 8.67–8.65 (m, 2H), 8.16 (d, 2H, J=6.6),7.90 (d, 2H, J=8.8), 7.16–7.09 (m, 4H), 6.82 (d, 2H, J=8.8), 4.26 (t,2H, J=6.2), 4.13 (t, 2H, J=6.2), 3.90 (dd, 1H, J=7.7, 4.8), 2.97 (dd,1H, J=14.3, 5.1), 2.83 (dd, 1H, J=14.3, 7.7), 2.24 (qn, 2H, J=5.9).

Example 273(2S)-2-Methoxy-3-{4-[3-(4-quinolin-8-yl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acidethyl ester (Example 270, Step A) and 8-quinoline boronic acid byfollowing the procedure described for Example 270 (Steps B and C).¹H-NMR (MeOD, 300.15 MHz): δ 8.82 (d, 1H, J=2.6), 8.39 (d, 1H, J=8.1),7.92 (d, 1H, J=7.9), 7.74–7.63 (m, 2H), 7.58–7.51 (m, 3H), 7.18 (d, 2H,J=8.5), 7.08 (d, 2H, J=8.7), 6.88 (d, 2H, J=8.7), 4.28 (t, 2H, J=6.0),4.20 (t, 2H, J=6.3), 3.90–3.80 (m, 1H), 3.30 (s, 3H), 3.04–2.84 (m, 2H),2.29 (qn, 2H, J=6.3).

Example 274(2S)-3-{4-[3-(4′-Cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

Step A(2S)-3-{4-[3-(4′-Cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester

(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 173, Step A) and 4′-hydroxy-4-biphenylcarbonitrile were treatedunder Mitsunobu standard conditions B (DIAD, toluene) to give the titlecompound. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.71–7.60 (m, 4H), 7.52 (d, 2H,J=8.9), 7.14 (d, 2H, J=8.9), 7.00 (d, 2H, J=8.9), 6.83 (d, 2H, J=8.6),4.24–4.12 (m, 6H), 3.90 (dd, 1H, J=7.3, 5.9), 3.34 (s, 3H), 2.97–2.93(m, 2H), 2.27 (qn, 2H, J=6.2), 1.23 (t, 3H, J=7.3).

Step B

(2S)-3-{4-[3-(4′-Cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-{4-[3-(4′-cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (Step A) via the standard hydrolysis procedure C(NaOH). ¹H-NMR (MeOD, 300.15 MHz): δ 7.77 (s, 4H), 7.64 (d, 2H, J=8.7),7.18 (d, 2H, J=8.5), 7.07 (d, 2H, J=8.7), 6.86 (d, 2H, J=8.3), 4.24 (t,2H, J=6.3), 4.17 (t, 2H, J=6.3), 3.84–3.74 (m, 1H), 3.03–2.81 (m, 2H),2.26 (qn, 2H, J=6.0).

Example 275(2S)-2-Methoxy-3-(4-{3-[4′-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-propoxy}-phenyl)-propionicacid

Step A(2S)-2-Methoxy-3-(4-{3-[4′-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-propoxy}-phenyl)-propionicacid ethyl ester

Azidotributyltin (0.72 mmol, 0.2 mL) was added to a solution of(2S)-3-{4-[3-(4′-cyano-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid ethyl ester (0.36 mmol, 0.17 g) (Example 274, Step A) in toluene (1mL). The mixture was heated at 60° C. for 48 hours. The mixture wasallowed to reach room temperature and 1N HCl was added. The mixture washeated at reflux for 24 additional hours. Upon cooling, water was addedand the aqueous phase was extracted with ethyl acetate. The organiclayer was dried (Na₂SO₄), filtered and evaporated. The crude product waspurified by chromatography on silica gel (hexanes/ethyl acetate/aceticacid 3.2:10%) to afford the title product. ¹H-NMR (CDCl₃, 200.15 MHz): δ8.12 (d, 2H, J=8.3), 7.65 (d, 2H, J=8.6), 7.51 (d, 2H, J=8.9), 7.11 (d,2H, J=8.6), 6.95 (d, 2H, J=8.6), 6.79 (d, 2H, 8.6), 4.25–4.06 (m, 7H),3.97 (dd, 1H, J=7.0, 5.4), 3.37 (s, 3H), 2.99–2.96 (m, 2H), 2.22 (qn,2H, J=5.9), 1.25 (t, 3H, J=7.2).

Step B

(2S)-2-Methoxy-3-(4-{3-[4′-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-propoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-2-methoxy-3-(4-{3-[4′-(1H-tetrazol-5-yl)biphenyl-4-yloxy]-propoxy}-phenyl)-propionicacid ethyl ester (Step A) via the standard hydrolysis procedure C(NaOH). ¹H-NMR (MeOD, 300.15 MHz): δ 8.09 (d, 2H, J=8.3), 7.70 (d, 2H,J=8.3), 7.62 (d, 2H, J=8.7), 7.18 (d, 2H, J=8.5), 7.05 (d, 2H, J=8.7),6.86 (d, 2H, J=8.7), 4.23 (t, 2H, J=6.0), 4.17 (t, 2H, J=6.1), 3.83 (dd,1H, J=8.3, 4.2), 3.36 (s, 3H), 2.99 (dd, 1H, J=14.1, 4.0), 2.84 (dd, 1H,J=13.9, 8.1), 2.26 (qn, 2H, J=6.3).

Example 276(2S)-3-{4-[3-(4-Imidazol-1-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 173, Step A) and 4-(imidazol-1-yl)phenol were treated underester J to give the title compound. ¹H-NMR (CDCl₃, 200.15 MHz): δ 8.11(s, 1H), 7.31–7.16 (m, 7H), 6.99 (d, 2H, J=8.9), 6.82 (d, 2H, J=8.6),4.19 (t, 2H, J=6.2), 4.12 (t, 2H, J=5.9), 3.95 (dd, 1H, J=7.3, 4.8),3.39 (s, 3H), 3.08 (dd, 1H, J=14.4, 4.8), 2.96 (dd, 1H, J=14.2, 7.6),2.26 (qn, 2H, J=5.9).

Example 277(2S)-3-(4-{3-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

The title compound was obtained from(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 173, Step A) and N-(4-hydroxyphenyl) phtalimide by followingthe procedure described for Example 276. ¹H-NMR (CDCl₃, 300.15 MHz): δ7.97–7.92 (m, 2H), 7.81–7.77 (m, 2H), 7.32 (d, 2H, J=8.9), 7.15 (d, 2H,J=8.5), 7.02 (d, 2H, J=8.9), 6.85 (d, 2H, J=8.5), 4.20 (t, 2H, J=6.0),4.16 (t, 2H, J=6.0), 3.99 (dd, 1H, J=7.3, 4.4), 3.41 (s, 3H), 3.11 (dd,1H, J=14.3, 4.4), 2.97 (dd, 1H, J=14.3, 7.1), 2.27 (qn, 2H, J=6.0).

Example 278(2S)-3-(4-{3-[4-(4-Acetyl-piperazin-1-yl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid

The title compound was obtained from(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 173, Step A) and 1-acetyl-4-(4-hydroxyphenyl)piperazine byfollowing the procedure described for Example 276. ¹H-NMR (CDCl₃, 300.15MHz): δ 7.14 (d, 2H, J=8.5), 6.90–6.80 (m, 5H), 4.15–4.09 (m, 3H), 3.98(dd, 1H, J=6.7, 4.9), 3.79–3.76 (m, 2H), 3.63–3.60 (m, 2H), 3.40 (s,3H), 3.11–2.93 (m, 6H), 2.14 (s, 3H).

Example 279(2S)-2-Methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}-propionicacid

Step A(2S)-2-Methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}-propionicacid ethyl ester

3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 173, Step A) and 1-(4-hydroxyphenyl)-piperazine were treatedunder ester K to give the title compound. ¹H-NMR (CDCl₃, 200.15 MHz): δ8.01 (s, 1H), 7.13 (d, 2H, J=8.6), 6.88–6.75 (m, 6H), 4.30 (t, 2H,J=6.4), 4.17 (q, 2H, J=7.0), 4.02 (t, 2H, J=5.9), 3.94–3.87 (m, 1H),3.64–3.60 (m, 4H), 3.34 (s, 3H), 2.98–2.96 (m, 4H), 2.18–2.04 (m, 2H),1.23 (t, 3H, J=7.3).

Step B

(2S)-2-Methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-2-methoxy-3-{4-[3-(4-piperazin-1-yl-phenoxy)-propoxy]-phenyl}-propionicacid ethyl ester (Step A) by standard hydrolysis procedure C (NaOH).¹H-NMR (MeOD 300.15 MHz): δ 7.18 (d, 2H, J=8.5), 6.89–6.83 (m, 4H), 6.72(d, 2H, J=9.1), 4.30 (t, 2H, J=6.3), 4.07 (t, 2H, J=6.1), 3.86–3.82 (m,1H), 3.62–3.59 (m, 4H), 3.36 (s, 3H), 3.07–2.83 (m, 6H), 2.12 (qn, 2H,J=6.3).

Example 280(2S)-2-Methoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}-propionicacid

Step A(2S)-2-Methoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}-propionicacid ethyl ester

A mixture of(2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acidethyl ester (1.03 mmol, 0.5 g), morpholine (1.24 mmol, 0.11 mL),Pd(OAc)₂ (0.05 mmol, 12 mg), 2,2′-bis(diphenylphsphino)-1,1′-binaphthyl(0.08 mmol, 48 mg) and cesium carbonate (1.45 mmol, 471 mg) in DMF (2mL) was heated at 110° C. for 14 hours. The mixture was purified througha silica gel column (hexanes/ethyl acetate 7:3) to afford the titlecompound. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.11 (d, 2H, J=8.8), 6.85 (broads, 2H), 6.80 (d, 4H, J=8.8), 4.21–4.04 (m, 6H), 3.91–3.80 (m, 5H), 3.32(s, 3H), 3.10–2.95 (m, 4H), 2.94–2.91 (m, 2H), 2.20 (qn, 2H, J=5.9),1.23 (t, 3H, J=7.2).

Step B

(2S)-2-Methoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-2-ethoxy-3-{4-[3-(4-morpholin-4-yl-phenoxy)-propoxy]-phenyl}-propionicacid ethyl ester (Step A) by standard hydrolysis procedure C (NaOH).¹H-NMR (CDCl₃, 200.15 MHz): δ 9.90 (s, 1H), 7.30 (d, 2H, J=9.1), 7.10(d, 2H, J=8.4), 6.91 (d, 2H, J=9.1), 6.75 (d, 2H, J=8.8), 4.18–3.90 (m,9H), 3.43–3.33 (m, 7H), 3.02 (dd, 1H, J=14.3, 4.8), 2.90 (dd, 1H,J=14.3, 7.0), 2.18 (qn, 2H, J=5.9).

Example 281(2S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-ethoxy-propionicacid

Step A3-[4-(3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-hydroxy-propionicacid

Boron tribromide (0.03 mmol, 0.03 mL) was added to a solution of3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionicacid (0.06 mmol, 25.5 mg) (Example 191) in CH₂Cl₂ (0.4 mL) at −78° C.The mixture was warmed to temperature gradually and stirred for 12hours. The solvent was concentrated to dryness to afford the titlecompound. ¹H-NMR (CDCl₃, 200.15 MHz): δ 7.56–7.18 (m, 8H), 6.99–6.95 (m,3H), 6.79–6.75 (m, 1H), 4.58–4.42 (m, 1H), 4.25–4.12 (m, 4H), 3.34–2.92(m, 2H), 2.30–2.22 (m, 2H).

Step B

3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-ethoxy-propionicacid

Ethyl iodide (0.6 mmol, 0.05 mL) was added to a solution of3-{4-[3-(biphenyl-4-yloxy)-propoxy]-2-chloro-phenyl}-2-hydroxy-propionicacid (Step A) and Ag₂O (0.09 mmol, 21 mg) in DMF (0.5 mL). The mixturewas heated at 50° C. for 24 hours. The mixture was warmed to roomtemperature, and 1N HCl was added until pH 3. The aqueous phase wasextracted with ethyl acetate (3×10 mL). The combined organic layers weredried (Na₂SO₄), filtered and evaporated. The crude was purified bychromatography on silica gel (CH₂Cl₂) to afford the title compound.¹H-NMR (CDCl₃, 300.15 MHz): δ 7.56–7.51 (m, 4H), 7.44–7.39 (m, 2H), 7.30(t, 1H, J=7.3), 7.20 (d, 1H, J=8.5), 6.99 (d, 2H, J=8.7), 6.95 (d, 1H,J=2.4), 6.77 (dd, 1H, J=8.5, 2.4), 4.21–4.13 (m, 5H), 3.64–3.54 (m, 1H),3.44–3.34 (m, 1H), 3.29 (dd, 1H, J=14.1, 4.2), 3.01 (dd, 1H, J=14.1,8.7), 2.28 (qn, 2H, J=6.0), 1.12 (t, 3H, J=6.9).

Example 2823-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-ethoxy-propionicacid

The title compound was prepared from3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionicacid (Example 193) by following the same procedure as in Example 281(Steps A and B). ¹H-NMR (CDCl₃, 300.15 MHz): δ 7.82 (d, 2H, J=8.7), 7.76(d, 2H, J=8.1), 7.61–7.55 (m, 1H), 7.50–7.45 (m, 2H), 7.18 (d, 1H,J=8.5), 6.99–6.95 (m, 3H), 6.77 (dd, 1H, J=8.5, 2.4), 4.25 (t, 2H,J=5.9), 4.17–4.14 (m, 3H), 3.61–3.38 (m, 2H), 3.29 (dd, 1H, J=14.1,4.9), 3.02 (dd, 1H, J=14.1, 8.1), 2.31 (qn, 2H, J=5.9), 1.14 (t, 3H,J=7.1).

Example 283(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

Step 1: (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester

The compound of (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid (5.1mmol) was dissolved in 50 ml of ethanol and 0.3 ml (5.6 mmol) ofsulfuric acid was added. The mixture was stirred at room temperature for18 hours and then concentrated. The mixture was diluted with water (55ml) and NaHCO₃ was added (310 mg, 3.7 mmol). This mixture was extractedwith ethyl acetate (4×20 mL), and the combined organic layers were dried(MgSO₄) and then concentrated to produce a yellow oil. ¹H-NMR (CDCl₃,200.15 MHz): 7.07 (d, 2H, J=8.6), 6.72 (d, 2H, J=8.6), 5.42 (br s, 1H),4.18 (q, 2H, J=7.3), 3.92 (dd, 1H, J=6.7, 5.9), 3.36 (s, 3H), 2.95 (d,2H, J=6.7), 1.23 (t, 3H, J=7.3).

Step 2: (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester

A mixture containing (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acidethyl ester obtained in Step 1 (0.223 mol, 50 mg), potassium carbonate(0.446 mol, 50 mg), magnesium sulfate (powdered, 50 mg, 1 g/g), ethylenedibromide (3.35 mol. 628 mg) and EtOH (25 mL) was heated at reflux(78–76° C.) for 24 hours and cool to room temperature. The mixture washeated again to reflux (76.5–77° C.) and 2 mL of ethylene dibromide wasadded. The mixture was heated for another 12 hours at 79.5–80.1° C. andthen cooled to room temperature and vacuum filtered. The filtrate wasconcentrated under vacuum, and the residue was purified by columnchromatography (silica gel, hexanes/ethyl acetate 6:1, Rf 027) toproduce a colorless oil. MS (ES) for C₁₄H₁₉BrO₄ [M+Na]⁺: 353.0.

Step 3:(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

A solution of biphenyl-4-ol (0.39 mmol, 68 mg) in 10 ml of DMF in wastreated with (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acidethyl ester obtained in Step 2 (0.33 mmol, 100 mg) and cesium carbonate(0.66 mmol, 214 mg) in a round bottom flask. The reactants were filteredand was washed with DMF several times and the solvent was evaporatedunder vacuo. The residue was reconstituted in a mixture of ethanol (20ml) and NaOH (1M) (8 ml), and then stirred at room temperature until TLCindicated the disappearance of starting material. Ethanol was removedunder vacuum, and the aqueous solution was diluted with 20 ml of brineand washed with diethyl ether (3×15 mL). The aqueous phase was acidifiedwith

1N HCl (pH 1–2) and extracted with ethyl acetate (3×15 mL). The organiclayer was dried (MgSO₄) and concentrated under vacuum to yield the titlecompound. MS (ES) for C₂₄H₂₄O₅ [M+Na]⁺: 415.4.

Example 284(2S)-2-methoxy-3-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-phenyl}-propionicacid

Step 1: 3-bromopropan-1-ol

The compound of 1,3-propanodiol (10.26 g, 134.8 mmol) was dissolved inbenzene (150 mL), and HBr 48% (16.84 mL) was added. The mixture wasrefluxed under aceotropic removal of water for 24 hours. The solvent wasdistilled at atmospheric pressure, and the residue was diluted withether and (150 mL) and washed with water (3×50) mL. The organic layerwas dried over MgSO₄ and concentrated to afford a yellowish oil. ¹H-NMR(CDCl₃, 200.15 MHz): 3.80 (t, 2H, J=6.4), 3.54 (t, 2H, J=6.5), 2.10 (qn,2H, J=6.4).

Step 2: (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acidethyl ester

A solution of triphenylphosphine (4.77 mmol, 1250 mg) in 50 mL of drytoluene was treated at 0° C. with diisopropilazodicarboxylate (4.77mmol, 964.5 mg) and stirred for about 20 minutes. A solution of(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (Example283, Step 1) (4.46 mmol, 1000 mg) and 3-bromo-propan-1-ol (4.77 mmol,663 mg) in 10 mL of dry THF was added, and the mixture was stirred atroom temperature overnight. The mixture was concentrated to drynessunder vacuum and purified by silica gel chromatography (silica gel,hexanes/ethyl acetate 6:1). The fraction with Rf 0.4 corresponding tothe coupled compound was combined and concentrated to dryness to afforda yellow oil. MS (ES) for C₁₅H₂₁BrO₄ [M+Na]⁺: 367.2.

Step 3:(2S)-2-methoxy-3-{4-[3-(3-trifluoromethyl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 3-trifluoromethyl-phenol via the sameprocedure used for the preparation of(2S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3) to produce a yellow solid.

MS (ES) for C₂₀H₂₁F₃O₅ [M+NH₄]⁺: 421.4.

Example 285 (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionicacid

A solution of (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionicacid ethyl ester (Example 284, Step 2) (0.1 mmol, 32 mg) in 0.7 ml of DMin a 16×100 mm tube was treated with phenol (0.15 mmol, 15 mg), cesiumcarbonate (0.3 mmol, 95 mg). The mixture was stirred at room temperatureovernight and the reactants were filtered and washed with DMF a severaltimes. The solvent was evaporated under vacuum, and the residue wasreconstituted in a mixture of ethanol (2 ml) and NaOH (1M, 1 ml), whichwas stirred at room temperature until temperature until reaction wascompleted by HPLC-MS. Upon completion, HCl (1M) was added pH=3) and thesolvents were eliminated under vacuum. The residue was reconstituted inCH₂Cl₂/H₂O and filtered through a hidrofobic syringer. The organic layerwas separated, concentrated and purified by HPLC-MS to afford the titlecompound as a colorless oil. MS (ES) for C₁₉H₂₂O₅ [M+NH₄]⁺: 348.4.

Example 286(2S)-3-{4-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and biphenyl-3-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₂₅H₂₅O₅[M+Na]+429.4.

Example 287(2S)-2-methoxy-3-{4-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 2-methyl-benzothiazol-5-ol via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid Example285, Step 1), to produce a colorless oil.

MS (ES) for C₂₁H₂₃NO₅S [M+H]⁺: 402.4.

Example 288(2S)-2-methoxy-3-{4-[3-(3-morpholin-4-yl-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 3-Morpholin-4-yl-phenol via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil.

MS (ES) for C₂₃H₂₉NO₆ [M+H]⁺: 416.4.

Example 289(2S)-2-methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 5,6,7,8-tetrahydro-naphthalen-2-ol via thesame procedure used for the: preparation of(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3), to produce a white solid.

MS (ES) for C₂₃H₂₈O₅ [M+Na]⁺: 402.4.

Example 2902-methoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 4-phenoxy-phenol via the same procedure usedfor the preparation of(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3) to produce a white solid.

MS (ES) for C₂₄H₂₄O₆ [M+NH₄]⁺: 426.0.

Example 2913-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 1)

Step 1: 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methylester

Sodium trimethylsilylamide 1M in THF (20.73 mL, 20.73 mmol) was added toa 2-neck round bottom flask under nitrogen. The flask was placed in anacetone bath cooled to about −78° C. A solution of methyl2-methoxyacetate (2.34 mL, 23.55 mmol) and 3-benzyloxybenzaldehyde (4.0g, 18.85 mmol) in dry THF (24 mL) was added dropwise via cannula over 10minutes. The mixture was stirred at −78° C. for 3 hours. HPLC-MS showedthe presence of starting aldehyde at this time. Additional 10 mL ofNaHDMS were added, and the mixture was stirred for another hour, andthen HCl 3N (50 mL) was added to the mixture at −78° C. The bath wasremoved, and the mixture was extracted with diethyl ether (4×50 mL). Thecombined organic layers were dried over MgSO₄ and concentrated to affordan oil that was purified by chromatography (silica gel, hexanes/ethylacetate 3:1). Rf. 0.13. (two isomers) ¹H-NMR (CDCl₃, 200.15 MHz):7.45–7.22 (m, 12H), 7.05–6.89 (m, 6H), 5.07 (d, 4H, J=1.1), 4.93 (dd,2H, J=11.8, 5.9), 3.97 (d, 1H, J=5.6), 3.89 (d, 1H, J=5.4), 3.67 (s,3H), 3.65 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H), 2.92 (br s, 1H), 2.83 (brs, 1H).

Step 2: 3-(3-benzyloxy-phenyl)-2-methoxy-acrylic acid methyl ester

The compounds of 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionicacid methyl ester (Example 291, Step 1) (4.06 g, 12.84 mmol),triethylamine (7.15 mL, 51.33 mmol) and 4-(N,N-dimethylamino)pyridine(0.157 g, 128 mmol) were dissolved in dichloromethane (20 mL) in a roundbottom flask and then cooled to 0° C. under ice bath. Mesyl chloride(1.093 mL, 14.1 mmol) was added dropwise via syringe, and the mixturewas stirred at room temperature until no starting aldol is observed byHPLC-MS (4 days, 0.2 additional mL of MsCl were added each day). Themixture was diluted with 200 mL of diethyl ether, washed with HCl (1N,3×40 mL) and 40 mL of brine, and dried over MgSO₄ Concentration of themixture afforded 3.96 g. of a 2.5:1 mixture of the acrylate and a singleisomer of the mesylate intermediate which was directly used in the nextStep. ¹H-NMR (CDCl₃, 200.15 MHz): 7.46–7.26 (m, 8H), 6.99–6.93 (m, 1H),5.10 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H).

Step 3: 3-(3-benzyloxy-phenyl)-2-methoxy-propionic acid methyl ester

A solution of 3-(3-benzyloxy-phenyl)-2-methoxy-acrylic acid methyl ester(Example 291, Step 2) (3.96 g) in methanol (10 mL) was placed in a roundbottom flask equipped with a reflux condenser. The mixture was cooled to0° C. and Mg turnings (6.45 g) were added. The mixture was initiallystirred vigorously and then further stirred at room temperature forabout an hour. The solvent was evaporated under vacuum, and 100 mL ofdiethyl ether were added to the resulting solid. HCl (3N, 100 mL) wasadded and the solution was stirred for one minute. The organic layer wasseparated from the slurry, and 100 mL of diethyl ether and HCl (3N, 100mL) were added to the remaining slurry. The procedure was repeated untilthe entire solid was dissolved. The combined ethereal extracts werewashed with brine and dried over MgSO₄. Concentration of the mixtureafforded a yellow oil which was about 90% pure bye NMR. ¹H-NMR (CDCl₃,200.15 MHz): 7.45–7.17 (m, 6H), 6.88–6.81 (m, 3H), 5.05 (s, 2H), 3.97(dd, 1H, J=7.3, 5.4), 3.72 (s, 3H), 3.34 (s, 3H), 3.00 (d, 1H, J=5.1),2.99 (d, 1H, J=7.8).

Step 4: 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester

The compounds of 3-(3-benzyloxy-phenyl)-2-methoxy-propionic acid methylester (Example 291, Step 3) (3.15 g, 10.49 mmol) and Pd 10% on activatedcarbon (0.558 g, 0.524 mmol) were placed in a 250-ml round bottom flaskequipped with a magnetic stirring bar. 100 mL of methanol was added, andhydrogen was bubbled through the solution for 10 minutes. The flask wassealed with a rubber septum, and a balloon containing 250 mL of hydrogenwas connected to the flask through a needle. The mixture was stirred atroom temperature for 5 hours and then concentrated to dryness undervacuum. The residue was taken up in ethyl acetate and filtered through apad of celite. Concentration of the mixture afforded an oil, ¹H-NMR(CDCl₃, 200.15 MHz): 7.15 (dt, 1H, J=1.1, 7.0), 6.79–6.68 (m, 3H), 5.27(br s, 1H), 3.98 (dd, 1H, J=7.5, 5.6), 3.73 (s, 3H), 3.35 (s, 3H), 2.97(d, 1H, J=3.8), 2.97 (d, 1H, J=9.1).

Step 5: [1,3,2]dioxathiane 2,2-dioxide

Thionyl chloride (36 mL, 491 mmol) was, added to a solution of1,3-propanodiol (30 g, 394 mmol) in CCl₄ (278 mL) via syringe. Themixture was heated at reflux for 1.5 hours and cooled to 0° C. toevaporate the solvent under vacuum. The residue was dissolved in amixture of CCl₄/CH₃CN/H₂O (2:2:3=500 mL) and cooled to 0° C. Rutheniumtrichloride trihydrate (0.556 g, 2.68 mmol) was added followed byaddition of solid NaIO₄ (14.35 g, 197 mmol). The mixture was stirred atroom temperature for 1 hour and then H₂O (1 L) was added. The aqueousphase was extracted with diethyl ether (4×300 mL). The combined organiclayers were washed with brine (2×100 mL), dried (MgSO₄), and filteredthrough a pad of silica gel to remove the ruthenium salts. The solventwas evaporated, and hexanes (200 mL) was added to the resulting oil.After cooling, a gray solid was precipitated, which was filtered andwashed with hexanes. Recrystallization from hexanes/ether yielded awhite crystaline solid. ¹H-NMR (200.15 MHz, CDCl₃): d 4.73 (t, 4H,J=5.6), 2.13 (qn, 2H, J=5.6).

Step 6: 3-(biphenyl-4-yloxy)-propan-1-ol

A solution of 4-phenylphenol (4.9 g, 29.0 mmol) and potassiumtert-butoxide (3.64 g, 30.3 mmol) in THF (100 mL) was stirred at roomtemperature for 30 minutes. The solution was cooled at 0° C. and[1,3,2]dioxathiane 2,2-dioxide (Example 291, Step 5) (3.6 g, 26.34 mmol)in THF (25 mL) was added. The mixture was stirred at room temperaturefor 5 hours, and the solvent was removed under vacuum. The residue wasdissolved in 6N HCl (15 mL) and heated at 100° C. for 16 hours. Themixture was cooled to room temperature, and the aqueous phase wasextracted with ethyl acetate (3×30 mL). The combined organic layers werewashed with H₂O (3×25 mL) and brine (25 mL), dried (MgSO₄), filtered,and concentrated to produce a white solid. ¹H-NMR (200.15 MHz, CDCl₃): d7.57–7.49 (m, 4H), 7.45–7.37 (m, 3H), 6.98 (dd, 2H, J=6.72, 2.14), 4.17(t, 2H, J=5.9), 3.88 (q, 2H, J=5.9), 2.07 (qn, 2H, J=5.9).

Step 7: 4-(3-bromo-propoxy)-biphenyl

Triphenylphosphine (1.61 g, 6.14 mmol) was added to a solution of3-(biphenyl-4-yloxy)-propan-1-ol (Example 291, Step 6) (1.00 g, 4.38mmol) and carbon tetrabromide (1.81 g, 5.47 mmol) in CH2Cl2 (20 mL) at0° C. The mixture was warmed to room temperature and stirred for aboutan hour and then extracted with ethyl acetate (50 mL). The organic layerwas washed with H₂O (3×50 mL) and brine (3×25 mL), and then dried(MgSO₄), filtered and concentrated. The crude product was purified bysilica gel column chromatography (silica gel, hexanes/ethyl acetate,9:1) to produce 4-(3-bromo-propoxy)-biphenyl. ¹H-NMR (200.15 MHz,CDCl₃): d 7.57–7.29 (m, 7H), 6.98 (dd, 2H, J=6.72, 1.88), 4.45 (t, 2H,J=5.92), 3.62 (t, 2H, J=6.44), 2.34 (qn, 2H, J=5.92).

Step 8: 3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid (Isomer 1)

The title compound was prepared from 4-(3-bromo-propoxy)-biphenyl(Example 291, Step 7) and 3-(3-hydroxy-phenyl)-2-methoxy-propionic acidmethyl ester (Example 291, Step 4) (0.3 g, 1.42 mmol) via the sameprocedure used for the preparation of(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3). The crude material was submitted to chiral HPLCseparation to afford the single enantiomer of isomer 1. ¹H-NMR (CDCl₃,200.15 MHz): 7.57–7.17 (m, 7H), 6.99 (dd, 2H, J=6.7, 2.2), 6.85–6.80 (m,3H), 4.19 (dd, 4H, J=13.4, 6.4), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s,3H), 0.14 (dd, 1H, J=14.0, 4.3), 2.98 (dd, 1H, J=14.8, 7.5), 2.28 (qui,2H, J=5.9).

Example 2923-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid(Isomer 2)

The title compound was prepared from 4-(3-bromo-propoxy)-biphenyl(Example 291, Step 7), and 3-(3-hydroxy-phenyl)-2-methoxy-propionic acidmethyl ester (Example 291, Step 4) via the same procedure used for thepreparation of(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3). The crude material was submitted to chiral HPLCseparation to afford the single enantiomer of isomer 2. ¹H-NMR (CDCl₃,200.15 MHz): 7.57–7.17 (m, 7H), 6.99 (dd, 2H, J=6.7, 2.2), 6.85–6.80 (m,3H), 4.19 (dd, 4H, J=13.4, 6.4), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s,3H), 0.14 (dd, 1H, J=14.0, 4.3), 2.98 (dd, 1H, J=14.8, 7.5), 2.28 (qn,2H, J=5.9).

Example 293(2S)-3-{4-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 2-hydroxy-benzonitrile via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil.

MS (ES) for C₂₀H₂₁NO₅ [M+NH₄]⁺: 373.4.

Example 294(2S)-2-methoxy-3-{4-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 2-methoxy-phenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₂₀H₂₄O₆ [M+NH₄]⁺:378.4.

Example 295(2S)-2-{3-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 2-hydroxy-benzoic acid methyl ester via thesame procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil.

MS (ES) for C₂₀H₂₂O₇ [M+H]⁺: 375.2.

Example 296(2S)-3-{4-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 3-hydroxy-benzonitrile via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil.

MS (ES) for C₂₀H₂₁NO₅ [M+NH₄]⁺: 373.4.

Example 297(2S)-3-{4-[3-(3-dimethylamino-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 3-dimethylamino-phenol via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil.

MS (ES) for C₂₁H₂₇NO₅ [M+H]⁺: 374.4.

Example 298(2S)-3-{3-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 3-hydroxy-benzoic acid methyl ester via thesame procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil.

MS (ES) for C₂₀H₂₂O₇ [M+Na]⁺: 397.4.

Example 299(2S)-3-{4-[3-(indan-5-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and indan-5-ol via the same procedure used for thepreparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionicacid (Example 285, Step 1), to produce a colorless oil.

MS (ES) for C₂₂H₂₆O₅ [M+Na]⁺: 393.4.

Example 300(2S)-2-methoxy-3-{4-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl esterExample 284, Step 2) and naphthalen-2-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₂₃H₂₄O₅ [M+Na]⁺:403.4.

Example 301(2S)-3-{4-[3-(1H-indol-5-yloxy-propoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 1H-indol-5-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₂₁H₂₃O₅ [M+H]⁺:370.4.

Example 302(2S)-2-methoxy-3-{4-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and quinolin-6-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₂₂H₂₃NO₅ [M+H]⁺:382.4.

Example 303(2S)-2-methoxy-3-{4-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 3-methoxy-phenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₂₀H₂₄O₆ [M+H]⁺:361.4.

Example 304(2S)-3-{4-[3-(3-fluoro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2) and 3-fluoro-phenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₁₉H₂₁FO₅ [M+Na]⁺:371.4.

Example 305(2S)-3-{4-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(example 284, Step 2) and 2-isopropyl-phenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (example285, Step 1), to produce a colorless oil. MS (ES) for C₂₂H₂₈O₅ [M+NH₄]⁺:390.4.

Example 306 (2S)-2-methoxy-3-[4-(2-phenoxy-ethoxy)-phenyl]-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl esterExample 283, Step 2) and phenol via the same procedure used for thepreparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionicacid (Example 285, Step 1), to produce a white solid. MS (ES) forC₁₈H₂₀O₅ [M+Na]⁺: 339.3.

Example 307(2S)-3-{4-[2-(2-cyano-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 2-hydroxy-benzonitrile via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil.

MS (ES) for C₁₉H₁₉NO₅ [M−H]⁻: 340.3.

Example 308(2S)-2-methoxy-3-{4-[2-(2-methoxy-phenoxy)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 2-methoxy-phenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₁₉H₂₂O₆ [M+Na]⁺:369.4.

Example 309(2S)-3-{4-[2-(biphenyl-2-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and biphenyl-2-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₂₄H₂₄O₅ [M+Na]⁺:415.4.

Example 310(2S)-2-{2-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-ethoxy}-benzoic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 2-hydroxy-benzoic acid methyl ester via thesame procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₁₉H₂₀O₇ [M+Na]⁺:383.3.

Example 311(2S)-3-{4-[2-(2-isopropyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 2-isopropyl-phenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₂₁H₂₆O₅ [M+Na]⁺:381.4.

Example 312(2S)-3-{4-[2-(3-cyano-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 3-hydroxy-benzonitrile via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid.

MS (ES) for C₁₉H₁₉NO₅ [M−H]⁻: 340.3.

Example 313(2S)-3-{4-[2-(3-dimethylamino-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 3-dimethylamino-phenol via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a yellow oil.

MS (ES) for C₂₁H₂₆O₅ [M+H]⁺: 360.4.

Example 314(2S)-3-{4-[2-(biphenyl-3-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(example 283, Step 2) and biphenyl-3-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid. (Example285, Step 1), to produce a white solid. MS (ES) for C₂₄H₂₄O₅ [M−H]⁻:391.4.

Example 315(2S)-3-{2-[4-(2-carboxy-2-methoxy-ethyl)-phenoxy]-ethoxy}-benzoic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 3-hydroxy-benzoic acid methyl ester via thesame procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid.

MS (ES) for C₁₉H₂₀O₇ [M−H]⁻: 359.3.

Example 316(2S)-3-{4-[2-(indan-5-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and indan-5-ol via the same procedure used for thepreparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionicacid (Example 285, Step 1), to produce a colorless oil. MS (ES) forC₂₁H₂₄O₅ [M−H]⁻: 355.3.

Example 317(2S)-2-methoxy-3-{4-[2-(naphthalen-2-yloxy)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and naphthalen-2-ol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₂₂H₂₂O₅ [M+NH₄]⁺:389.3.

Example 318(2S)-2-Methoxy-3-{4-[2-(quinolin-6-yloxy)-ethoxy]-phenyl}-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and quinolin-6-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₂₁H₂₁NO₅ [M+H]⁺:368.3.

Example 319(2S)-2-Methoxy-3-{4-[2-(3-morpholin-4-yl-phenoxy)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 3-morpholin-4-yl-phenol via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a yellow oil.

MS (ES) for C₂₂H₂₇NO₆ [M+H]+402.4.

Example 320(2S)-2-methoxy-3-{4-[2-(2-methyl-benzothiazol-5-yloxy)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 2-methyl-benzothiazol-5-ol via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a yellow oil.

MS (ES) for C₂₀H₂₁NO₅S [M+H]⁺: 388.3.

Example 321(2S)-2-methoxy-3-{4-[2-(3-methoxy-phenyl)-ethoxy]-phenyl}-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 3-methoxy-phenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₁₉H₂₂O₆ [M−H]⁻:345.3.

Example 322(2S)-3-{4-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 3-fluoro-phenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₁₈H₁₉FO₅ [M−H]⁻:333.3.

Example 323 2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propionic acid(isomer 1)

Step 1: 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methylester

The title compound was prepared from 3-bromo-propan-1-ol (Example 284,Step 1) and 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester(Example 291, Step 4) via the same procedure used for the preparation of(2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 284, Step 2). ¹H-NMR (CDCl₃, 200.15 MHz): 7.26–7.16 (m, 1H),6.80 (t, 3H, J=7.3), 4.09 (t, 2H, J=5.9), 3.97 (dd, 1H, J=7.3, 5.4),3.73 (s, 3H), 3.60 (t, 2H, J=6.4), 3.36 (s, 3H), 3.00 (s, 1H), 2.97 (d,1H, J=3.2), 2.31 (qn, 2H, J=6.2).

Step 2: (Isomer-1) 2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propionicacid

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and phenol via the same procedure used for thepreparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionicacid (Example 285, Step 1). The enatiomers were separated by chiralHPLC. MS (ES) for C₁₉H₂₂O₅ [M+Na]⁺: 353.3.

Example 3243-{3-[3-(2-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-cianophenol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₁NO₅ [M+Na]⁺: 378.3.

Example 3253-{3-[3-(3-cyano-phenoxy)-propoxy-]phenyl}-2-methoxy-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl esterExample 323, Step 1) and 3-cianophenol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₁NO₅ [M+Na]⁺: 378.3.

Example 326 2-methoxy-3-[3-(3-phenoxy-propoxy)-phenyl]-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and phenol via the same procedure used for thepreparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionicacid (Example 285, Step 1). The enantiomers were separated by chiralHPLC.

MS (ES) for C₁₉H₂₂O₅ [M+Na]⁺: 353.3.

Example 3273-{3-[3-(2-cyano-phenyl)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-cianophenol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₁NO₅ [M+Na]⁺: 378.3

Example 3283-{3-[3-(3-cyano-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 3-cianophenol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₁NO₅ [M+Na]⁺: 378.3

Example 3292-methoxy-3-{3-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-methoxyphenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₄O₆ [M+Na]⁺: 383.4.

Example 3302-methoxy-3-{3-[3-(2-methoxy-phenoxy)-propoxy]-phenyl}-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-methoxyphenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₄O₆ [M+Na]⁺: 383.4.

Example 3313-{3-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-isopropylphenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₂H₂₈O₅ [M+Na]⁺: 395.4.

Example 3323-{3-[3-(2-isopropyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 2)

The title compound-was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-isopropylphenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₂H₂₈O₅ [M+Na]⁺: 395.4.

Example 333 3-{3-[3-2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoicacid (isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 3-hydroxybenzoic acid methyl ester via thesame procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₂O₇ [M+Na]⁺: 397.4.

Example 3343-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 3-hydroxybenzoic acid methyl ester via thesame procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₂O₇ [M+Na]⁺: 397.4.

Example 3352-methoxy-3-{3-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(example 323, Step 1) and 3-methoxyphenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₄O₆ [M+Na]⁺: 383.3.

Example 3362-methoxy-3-{3-[3-(3-methoxy-phenoxy)-propoxy]-phenyl}-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 3-methoxyphenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₄O₆ [M+Na]⁺: 383.3.

Example 3372-methoxy-3-{3-[3-(naphthalen-2-yloxy)-propoxy]-phenyl}-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-naphthol via the same procedure used for thepreparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionicacid (Example 285, Step 1). The enatiomers were separated by chiralHPLC.

¹H-NMR (CDCl₃, 200.15 MHz): 7.78–7.69 (m, 3H), 7.47–7.12 (m, 5H),6.84–6.81 (m, 3H), 4.28 (t, 2H, J=5.9), 4.19 (t, 2H, J=5.9), 4.02 (dd,1H, J=7.5, 4.0), 3.38 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.3), 2.97 (dd, 1H,J=14.2, 7.5), 2.33 (qn, 2H, J=6.2). MS (ES) for C₂₃H₂₄O₅ [M+H]⁺: 381.2.

Example 3382-methoxy-3-{3-[3-naphthalen-2-yloxy)-propoxy]-phenyl}-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-naphthol via the same procedure used for thepreparation, of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC.

¹H-NMR (CDCl₃, 200.15 MHz): 7.78–7.69 (m, 3H), 7.47–7.12 (m, 5H),6.84–6.81 (m, 3H), 4.28 (t, 2H, J=5.9), 4.19 (t, 2H, J=5.9), 4.02 (dd,1H, J=7.5, 4.0), 3.38 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.3), 2.97 (dd, 1H,J=14.2, 7.5), 2.33 (qn, 2H, J=6.2). MS (ES) for C₂₃H₂₄O₅ [M+H]⁺: 381.2.

Example 3392-methoxy-3-{3-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}-propionicacid (isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-methyl-benzothiazol-5-ol via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₁H₂₃NO₅S [M+H]⁺: 402.1.

Example 3402-methoxy-3-{3-[3-(2-methyl-benzothiazol-5-yloxy)-propoxy]-phenyl}-propionicacid (isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-methyl-benzothiazol-5-ol via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₁H₂₃NO₅S [M+H]⁺: 402.1.

Example 3413-{3-[3-(2-chloro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-chlorophenol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. ¹H-NMR(CDCl₃, 200.15 MHz): 7.35 (dd, 1H, J=8.1, 1.9), 7.24–7.16 (m, 2H),6.97–6.80 (m, 5H), 4.22 (t, 2H, J=5.9), 4.20 (t, 2H, J=5.9), 4.02 (dd,1H, J=7.3, 4.0), 3.39 (s, 3H), 3.13 (dd, 1H, J=14.2, 3.8), 2.97 (dd, 1H,J=14.0, 7.8), 2.30 (qn, 2H, J=6.2).

MS (ES) for C₁₉H₂₁ClO₅ [M+Na]⁺: 387.2.

Example 3423-{3-[3-(2-chloro-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-chlorophenol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. ¹H-NMR(CDCl₃, 200.15 MHz): 7.35 (dd, 1H, J=8.1, 1.9), 7.24–7.16 (m, 2H),6.97–6.80 (m, 5H), 4.22 (t, 2H, J=5.9), 4.20 (t, 2H, J=5.9), 4.02 (dd,1H, J=7.3, 4.0), 3.39 (s, 3H), 3.13 (dd, 1H, J=14.2, 3.8), 2.97 (dd, 1H,J=14.0, 7.8), 2.30 (qn, 2H, J=6.2).

MS (ES) for C₁₉H₂₁ClO₅ [M+Na]⁺: 387.2.

Example 3433-{3-[3-(3,4-dimethyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 3,4-dimethylphenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. ¹H-NMR(CDCl₃, 200.15 MHz): 7.18 (d, 1H, J=7.5), 7.02 (d, 1H, J=8.3), 6.84–6.62(m, 5H), 4.14 (t, 2H, J=6.4), 4.12 (t, 2H, J=5.9), 4.02 (dd, 1H, J=7.3,4.0), 3.39 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.97 (dd, 1H, J=14.0,7.5), 2.23 (q, 1H, J=6.2.1), 2.22 (s, 3H), 2.18 (s, 3H). MS (ES) forC₂₁H₂₆O₅ [M+Na]⁺: 381.2.

Example 3443-{3-[3-(3,4-dimethyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 3,4-dimethylphenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. ¹H-NMR(CDCl₃, 200.15 MHz): 7.18 (d, 1H, J=7.5), 7.02 (d, 1H, J=8.3), 6.84–6.62(m, 5H), 4.14 (t, 2H, J=6.4), 4.12 (t, 2H, J=5.9), 4.02 (dd, 1H, J=7.3,4.0), 3.39 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.97 (dd, 1H, J=14.0,7.5), 2.23 (q, 1H, J=6.2.1), 2.22 (s, 3H), 2.18 (s, 3H). MS (ES) forC₂₁H₂₆O₅ [M+Na]⁺: 381.2.

Example 3452-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-hydroxy-benzoic acid via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₂O₇ [M+H]⁺: 375.2.

Example 3462-{3-[3-(2-carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-benzoic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and 2-hydroxy-benzoic acid via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₀H₂₂O₇ [M+H]⁺: 375.2.

Example 3473-{3-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and biphenyl-3-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₅H₂₆O₅ [M+Na]⁺: 429.2.

Example 3483-{3-[3-(biphenyl-3-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and biphenyl-3-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₅H₂₆O₅ [M+Na]⁺: 429.2.

Example 3492-methoxy-3-{3-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionic acid(isomer 1)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 323, Step 1) and quinolin-6-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₂H₂₃NO₅ [M+H]⁺: 382.2.

Example 3502-methoxy-3-{3-[3-(quinolin-6-yloxy)-propoxy]-phenyl}-propionic acid(isomer 2)

The title compound was prepared from3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl esterExample 323, Step 1) and quinolin-6-ol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₂H₂₃NO₅ [M+H]⁺: 382.2.

Example 3513-{3-[2-(2-isopropyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(isomer 2)

Step 1: 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methylester

The title compound was prepared from3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291,Step 4) (4.76 mol, 1000 mg) via the same procedure used for thepreparation of (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionicacid ethyl ester (Example 283, Step 2). MS (ES) for C₁₃H₁₇BrO₄ [M+NH₄]⁺:334:2.

Step 2:3-{3-[2-(2-isopropyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(isomer 2)

The title compound was prepared from 2-isopropyl-phenol and3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 351, Step 1) via the same procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₁H₂₆O₅ [M−H]⁻:357.2.

Example 3522-methoxy-3-{3-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propionic acid(isomer 1)

The title compound was prepared from 3-methoxy-phenol and3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 351, Step 1) via the same procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₁₉H₂₂O₆ [M−H]⁻: 345.1.

Example 3533-{3-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(isomer 1)

The title compound was prepared from 3-fluoro-phenol and3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 351, Step 1) via the same procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₁₈H₁₉FO₅ [M−H]⁻: 333.1.

Example 3542-methoxy-3-{3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy-ethoxy]-phenyl}-propionicacid (isomer 1)

The title compound was prepared from 5,6,7,8-tetrahydro-naphthalen-2-oland 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 351, Step 1) via the same procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₂H₂₆O₅ [M−H]⁻: 369.2.

Example 3552-methoxy-3-{3-[2-(3-methoxy-phenoxy)-ethoxy]-phenyl}-propionic acid(isomer 2)

The title compound was prepared from 3-methoxy-phenol and3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 351, Step 1) via the same procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₁₉H₂₂O₆ [M−H]³¹: 345.1.

Example 3563-{3-[2-(3-fluoro-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(isomer 2)

The title compound was prepared from 3-fluoro-phenol and3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 351, Step 1) via the same procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid(Example-285, Step 1). The enatiomers were separated by chiral HPLC. MS(ES) for C₁₈H₁₉FO₅ [M−H]⁻: 333.1.

Example 3572-methoxy-3-{3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethoxy]-phenyl}-propionicacid (isomer 2)

The title compound was prepared from 5,6,7,8-tetrahydro-naphthalen-2-oland 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester(Example 351, Step 1) via the same procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) forC₂₂H₂₆O₅ [M−H]⁻: 369.2.

Example 358(2S)-2-methoxy-3-{4-[2-(4-trifluoromethyl-phenoxy)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 4-trifluoromethyl-phenol via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid.

MS (ES) for C₁₉H₁₉F₃O₅ [M+Na]⁺: 407.2.

Example 359(2S)-2-methoxy-3-(4-{2-[4-(1-methyl-1-phenyl-ethyl)-phenoxy]-ethoxy}-phenyl)-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 4-(1-methyl-1-phenyl-ethyl)-phenol via thesame procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid.

MS (ES) for C₂₇H₃₀O₅ [M+Na]⁺: 457.2.

Example 360(2S)-3-{4-[2-(4-benzyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 4-benzyl-phenol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₂₅H₂₆O₅ [M+Na]⁺:429.3.

Example 361(2S)-2-methoxy-3-{4-[2-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 7-hydroxy-2-phenyl-chromen-4-one via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a yellow solid.

MS (ES) for C₂₇H₂₄O₇ [M+H]⁺: 461.3.

Example 362(2S)-3-{4-[2-(4-cyclopentyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 1-cyclopentyl-4-methoxy-benzene via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid.

MS (ES) for C₂₃H₂₈O₅ [M+Na]⁺: 407.3.

Example 363(2S)-3-{4-[2-(9H-fluoren-2-yloxy)-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 9H-fluoren-2-ol via the same procedure usedfor the preparation of(2S)-2-methoxy-3-[(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₂₅H₂₄O₅ [M+Na]⁺:427.3.

Example 364(2S)-3-[4-(2-butyl-phenoxy)-ethoxy-phenyl]-2-methoxy-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 4-butyl-phenol via the same procedure used forthe preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS(ES) for C₂₂H₂₈O₅ [M+Na]⁺:395.3.

Example 365(2S)-3-{4-[2-(2′-fluoro-biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 2′-fluoro-biphenyl-4-ol via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid.

MS (ES) for C₂₄H₂₃FO₅ [M+Na]⁺: 433.3.

Example 366(2S)-3-(4-{2-[4-(2,2-dimethyl-propionyl)-phenoxy]-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 1-(4-hydroxy-phenyl)-2,2-dimethyl-propan-1-onevia the same procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil. MS (ES) for C₂₃H₂₈O₆ [M+H]⁺:401.4.

Example 3673-(4-{2-[4-(2,2-dimethyl-propionylamino)-phenoxy]-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and N-(4-hydroxy-phenyl)-2,2-dimethyl-propionamidevia the same procedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₂₃H₂₉NO₆ [M+H]⁺:416.4.

Example 368(2S)-3-(4-{2-[4-(cyclopentanecarbonyl-amino)-phenoxy]-ethoxy}-phenyl)-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and cyclopentanecarboxylic acid(4-hydroxy-phenyl)-amide via the same procedure used for the preparationof (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid(Example 285, Step 1), to produce a white solid. MS (ES) for C₂₄H₂₉NO₆[M+H]⁺: 428.3.

Example 369(2S)-3-[4-(2-{4-[(furan-2-carbonyl)-amino]-phenoxy}-ethoxy)-phenyl]-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and furan-2-carboxylic acid(4-hydroxy-phenyl)-amide via the same procedure used for the preparationof (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid(Example 285, Step 1) to produce a white solid. MS (ES) for C₂₃H₂₃NO₇[M+H]⁺: 426.3.

Example 370(2S)-2-methoxy-3-[4-(2-{4-[(pyridine-3-carbonyl)-amino]-phenoxy}-ethoxy)-phenyl]-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and N-(4-hydroxy-phenyl)-nicotinamide via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid. MS (ES) for C₂₄H₂₄N₂O₆ [M+H]+:437.3.

Example 371(2S)-2-methoxy-3-{4-[2-(2-pyrrolidin-1-yl-phenoxy)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 2-pyrrolidin-1-yl-phenol via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a yellow oil.

MS (ES) for C₂₂H₂₇NO₅ [M+H]⁺: 386.3.

Example 372(2S)-2-methoxy-3-{4-[2-(pyridin-2-yloxy)-ethoxy]-phenyl}-propionic acid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and pyridin-2-ol via the same procedure used forthe preparation of(2S)-2-Methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1); to produce a colorless oil. MS (ES) for C₁₇H₁₉NO₅ [M+H]⁺:318.3.

Example 373(2S)-2-methoxy-3-{4-[2-(2-morpholin-4-yl-phenoxy)-ethoxy]-phenyl}-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) and 2-morpholin-4-yl-phenol via the same procedureused for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a colorless oil.

MS (ES) for C₂₂H₂₇NO₆ [M+H]⁺: 402.3.

Example 374(2S)-3-{4-[2-(4′-tert-butyl-biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionicacid

The title compound was prepared from(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl esterExample 283, Step 2) and 4′-tert-butyl-biphenyl-4-ol via the sameprocedure used for the preparation of(2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example285, Step 1), to produce a white solid.

MS (ES) for C₂₈H₃₂O₅ [M−H]⁻: 447.2.

Example 375(2S)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic acid

Step 1: 3-(4-benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethylester

The title compound was preoared from 4-benzyloxybenzaldehyde, lithiumdiisopropylamide and ethyl 2-ethoxyacetate via the same procedure usedfor the preparation of 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxypropionic acid methyl ester (Example 291, Step 1). MS (ES) for C₂₀H₂₄O₅[M+H₂O−H]⁺: 327, [M+Na]⁺: 367.4.

Step 2: 3-(4-benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl ester

The title compound was prepared from3-(4-benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester(Example 375, Step 1) via the same procedure used for the preparation of3-(4-benzyloxy-phenyl)-2-ethoxy-acrylic acid methyl ester. MS (ES) forC₂₀H₂₂O₄ [M+H]⁺: 327.2.

Step 3: 3-(4-benzyloxy-phenyl)-2-ethoxy-propionic acid methyl ester

The title compound was prepared from3-(4-benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl ester (Example 375,Step 2) (3.3 gr, 10.12 mmol) via the same procedure used for thepreparation of 3-(3-benzyloxy-phenyl)-2-methoxy-propionic acid methylester (Example 291, Step 3) to produce an oil that was purified bychromatography (silica gel, hexanes/ethyl acetate 6:1) to produce twocompounds: 3-(4-benzyloxy-phenyl)-propionic acid methyl ester (1.5 gr,Rf aprox. 0.65) and the desired compound (1.5 gr, Rf aprox. 0.2).

MS (ES) for C₁₉H₂₂O₄ [M+NH₄]⁺: 332.3.

Step 4: 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid methyl ester

The title compound was prepared from3-(4-benzyloxy-phenyl)-2-ethoxy-propionic acid methyl ester (example375, Step 3) via the same procedure used for the preparation of3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291,Step 4) to produce a yellow oil. MS (ES) for C₁₂H₁₆O₄ [M+H]⁺: 225.2,[M+NH₄]⁺: 242.2, [M+Na]⁺: 247.2.

Step 5: 4-(2-bromo-ethoxy)-phenoxyphenyl

The title compound was prepared from 4-phenoxy-phenol via the sameprocedure used for the preparation of(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) to produce a white solid. MS (ES) for C₁₄H₁₃BrO₂[M−H]⁻: 291.0.

Step 6:(2S)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic acid

The title compound was prepared from2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid methyl ester Example 375,Step 4) and 4-(2-bromo-ethoxy)-phenoxyphenyl (Example 375, Step 5) viathe same procedure used for the preparation of(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3). The crude material was submitted to chiral HPLCseparation to afford the single enantiomer isomer 2. MS (ES) forC₂₅H₂₆O₆ [M−H]⁻: 421.4.

Example 376(2R)-2-ethoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionic acid

The title compound was prepared from2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid methyl ester (Example 375,Step 4) and 4-(2-bromo-ethoxy)-phenoxyphenyl (Example 375, Step 5) viathe same procedure used for the preparation of(2S)-3-{4-[2-(biphenyl-4yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3). The crude material was submitted to chiral HPLCseparation to afford the single enantiomer isomer 1. MS (ES) forC₂₅H₂₆O₆ [M−H]⁻: 421.4.

Example 377(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-propoxy-propionic acid

Step 1: 4-(2-bromo-ethoxy)biphenyl

The title compound was prepared from biphenyl-4-ol via the sameprocedure used for the preparation of(2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester(Example 283, Step 2) to produce a white solid. MS (ES) for C₁₄H₁₃BrO[M−H]⁻: 279.1.

Step 2: (2S)-3-(4-benzyl-phenyl)-2-hydroxy-propionic acid ethyl ester

The title compound was prepared from(2S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid via the sameprocedure used for the preparation of(2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (Example283, Step 1) to afford the product as a yellow oil. ¹H-NMR (CDCl₃,200.15 MHz): 7.35–7.55 (m, 5H), 7.20 (d, 2H, J=8.3), 6.79 (d, 2H,J=8.3), 4.99 (s, 2H), 4.41 (dd, 1H, J=6.5, 4.4), 4.19 (c, 2H, J=6.9),2.92 (2dd, 2H, J=16.1, 4.4), 1.23 (t, 3H, J=6.9).

Step 3: (2S)-3-(4-benzyloxy-phenyl)-2-propoxy-propionic acid ethyl ester

Propyl iodide (41.6 mmol) was added at room temperature to a solution of(2S)-3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid ethyl ester(Example 377, Step 2) (8.3 mmol) and silver oxide (12.45 mmol) in 40 mLof DMF. The mixture was heated at 50° C. for 24 hours. After that themixture was cooled to room temperature, 300 ml of ethyl acetate and 200ml of water were added. The aqueous layer was separated and the organiclayer were washed with brine (3×100 ml), and then dried over (MgSO₄),filtered and concentrated under vacuum. The crude was purified bychromatography (silica gel, hexanes/ethyl acetate 6:1) to produce ayellow oil. ¹H-NMR (CDCl₃, 200.15 MHz): 7.42–7.31 (m, 5 H), 7.17 (d, 2H, J=8.6 Hz), 6.90 (d, 2 H, J=8.6 Hz), 5.05 (s, 2 H), 4.17 (q, 2 H,J=7.0 Hz), 3.97 (dd, 1 H, J=7.0, 6.2 Hz), 3.53 (dt, 1 H, J=8.9, 6.4 Hz),3.23 (dt, 1 H, J=9.1, 6.7 Hz), 2.97 (d, 2 H, J=6.7 Hz), 1.66–1.48 (m, 2H), 1.23 (t, 3 H, J=7.3 Hz), 0.86 (t, 3 H, J=7.5 Hz).

Step 4: (2S)-3-(4-hydroxy-phenyl)-2-propoxy-propionic acid ethyl ester

The title compound was prepared from (2S)-3-(4-beyloxy-phenyl)-2-propoxy-propionic acid ethyl ester (Example 377, Step 3)via the same procedure used for the preparation of3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291,Step 4) to produce a yellow oil. MS (ES) for C₁₄H₂₀O₄ [M+H]⁺: 253.1.

Step 5:(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-propoxy-propionic acid

The title compound was prepared from 4-(2-bromo-ethoxy)-biphenyl(Example 377, Step 1) and (2S)-3-(4-hydroxy-phenyl)-2-propoxy-propionicacid ethyl ester (Example 377, Step 4) via the same procedure used forthe preparation of(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3) to produce a white solid. MS (ES) for C₂₆H₂₈O₅[M+H]⁺: 421.0, [M+NH₄]⁺: 438.0, [M+Na]⁺: 443.0, [M−H]⁻: 3239.2.

Example 3783-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-ethoxy-propionic acid(isomer 1)

Step 1: 3-(3-benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethylester

The title compound was prepared from 3-benzyloxy-benzaldehyde and ethylethoxyacetate via the same procedure used for the preparation of3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester(Example 291, Step 1) to afford the title compound as a colorless oil.

Step 2: 3-(3-benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl ester

The title compound was prepared from3-(3-benzyloxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester(Example 378, Step 1) via the same procedure used for the preparation of3-(3-benzyloxy-phenyl)-2-methoxy-acrylic acid methyl ester (Example 291,Step 2) to afford the title compound as a colorless oil.

Step 3: 3-(3-benzyloxy-phenyl)-2-ethoxy-propionic acid methyl ester

The title compound was prepared from3-(3-benzyloxy-phenyl)-2-ethoxy-acrylic acid ethyl ester Example 378,Step 2) via the same procedure used for the preparation of3-(3-benzyloxy-phenyl)-2-methoxy-propionic acid methyl ester (Example291, Step 3) to afford the title compound as a colorless oil.

Step 4: 2-ethoxy-3-(3-hydroxy-phenyl)-propionic acid methyl ester

The title compound was prepared from3-(3-benzyloxy-phenyl)-2-ethoxy-propionic acid methyl ester (Example378, Step 3) via the same procedure used for the preparation of3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291,Step 4) to afford the title compound as a yellow oil. MS (ES) forC₁₂H₁₆O₄ [M+H]⁺: 225.1.

Step 5: (3-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-ethoxy-propionicacid (isomer 1)

The title compound was prepared from 3-(biphenyl-4-yloxy)-propan-1-ol(Example 291, Step 6) and 2-ethoxy-3-(3-hydroxy-phenyl)-propionic acidmethyl ester (Example 378, Step 4) via the same procedure used for thepreparation of(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3) to produce a white solid. The crude material wassubmitted to chiral HPLC separation to afford the single enantiomerisomer 1. (ES) for C₂₆H₂₈O₅ [M+NH₄]⁺: 438.0, [M+Na]⁺: 443.0.

Example 3793-{3-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-ethoxy-propionic acid(isomer 2)

The title compound was prepared from 3-(biphenyl-4-yloxy)-propan-1-ol(Example 291, Step 6) and 2-ethoxy-3-(3-hydroxy-phenyl)-propionic acidmethyl ester (Example 378, Step 4) via the same procedure used for thepreparation of(2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid(Example 283, Step 3) to produce a white solid. The crude material wassubmitted to chiral HPLC separation to afford the single enantiomerisomer 2. MS (ES) for C₂₆H₂₈O₅ [M+NH₄]⁺: 438.0, [M+Na]⁺: 443.0.

Example 380

Binding Assay:

DNA-dependent binding was carried out using Scintillation ProximityAssay (SPA) technology. PPARγ as well as its heterodimeric partner RXRαwere prepared using a baculovirus expression system. A biotinylatedcomplementary oligonucleotide duplex representing the human consensusPPR response element was used for binding receptor dimer to Yttriumsilicate streptavidin-coated SPA beads. The 5′-3′ strand had thesequence: ^(5′)TAATGTAGGTAATAGTTCAATAGGTCAAAGG^(3′) (SEQ ID NO: 1);biotin was bound to the first A at the 3′ end of the complementary 3′-5′strand. The PPARγ labeled ligand was³H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid with specific activity of 24 Ci/mmol. The binding assay was carriedout on 96 well dishes. Per well, 100 ng of oligonucleotide waspreincubated with 3 μg SPA beads in a binding buffer containing 10 mMHEPES pH 7.8, 80 mM KCl, 0.5 mM MgCl₂, 1 mM DTT, 0.5% CHAPS and 16.6 μgbovine serum albumin for 30 minutes at room temperature. The mixture wasthen spun at 2000 rpm for 3 minutes to pellet the beads-oligo mix. Thesupernatant was removed, and the beads-oligo pellet was resuspended inthe same binding buffer as above but also containing 14% glycerol, 5 μgsheared salmon sperm DNA and 2.5 μg of each receptor, PPARγ and RXRα. Asaturation binding assay was carried out using increasing amounts of³H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid in the reaction to obtain 0.39 nM to 402 nM of³H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid. Non-specific binding was measured in the presence of 10 μM ofunlabeled(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid. A K_(d) value was calculated from the saturation bindingexperiments after plotting specific binding versus concentration oflabeled ligand. Competition binding reactions were carried in thepresence of 30,000 cpm of³H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid and 5 nM to 10 μM of competing compounds. The IC₅₀ (nM) values forcompeting compounds were calculated after deduction of non-specificbinding (measured in the presence of 10 μM unlabeled³H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}2-methoxy-propionicacid), and the data normalized to total binding (if the absence of anyunlabeled compound). The³H-(s)-3-{4-[3-(biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy propionicacid was effective in determining the binding affinity of PPAR subtypesin the range of 5 nM to 10000 nM. For example, PPAR compounds with

IC₅₀ values less than 500 nM were identified as ligands for PPAR gamma.

Preparation of³H-(s)-3-{4-[3-(biphenyl-4-yloxy-propoxy]-phenyl}-2-methoxy-propionicacid

In a reaction vessel(s)-3-{4-[3-(4′-bromo-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid (6.1 mg) was combined with 10% Pd/CaCO₃ (18.6 mg), DMF (0.5 ml) andmethanol (0.5 ml). The mixture was stirred under 10 Ci of tritium gasfor about 4.5 hours. The catalyst was removed by filtration, and thelabile activity was removed by repeated rotary evaporations withmethanol. The final residue was dissolved in ethanol. The crude productwas purified by reverse phase HPLC eluting with a water/acetonitrile/TFAgradient system. The major UV and radioactive peak was collected androtary evaporated to dryness. The resulting residue was dissolved inethanol (yield: 102 mCi)

Example 381

Binding and Cotransfection Studies

The in vitro potency of compounds in modulating PPARα and PPARγreceptors were determined by the procedures detailed below.DNA-dependent binding (ABCD binding) was carried out using ScintillationProximity Assay (SPA) technology with PPAR receptors. Tritium-labeledPPARα and PPARγ agonists were used as radioligands for generatingdisplacement curves and IC₅₀ values with compounds of the presentinvention. Cotransfection assays were carried out in CV-1 cells. Thereporter plasmid contained an acylCoA oxidase (AOX) PPRE and TK promoterupstream of the luciferase reporter cDNA. Appropriate PPARs and RXRαwere constitutively expressed using plasmids containing the CMVpromoter. Since for PPARα and PPARβ/δ, interference by endogenous PPARγin CV-1 cells is an issue, in order to eliminate such interference, aGAL4 chimeric system was used in which the DNA binding domain of thetransfected PPAR is replaced by that of GAL4, and the GAL4 responseelement was utilized in place of the AOX PPRE. Cotransfection efficacywas determined relative to PPAR-isotope specific reference compounds.Efficacies were determined by computer fit to a concentration-responsecurve, or in some cases at a single high concentration of agonist (10μM). Typical range for concentration determination IC₅₀ is in the rangeof 1 nM to 10 μM. For binding or cotransfection studies with receptorsother than PPARs, similar assays were carried out using appropriateligands, receptors, reporter constructs for that particular receptor.

These studies were carried out to evaluate the ability of compounds ofthe present invention to bind to and/or activate various nucleartranscription factors, particularly huPPARα (“hu” indicates “human”) andhuPPARγ. These studies provided in-vitro data concerning efficacy andselectivity of compounds of the present invention. Furthermore, bindingand cotransfection data for compounds of the present invention werecompared with corresponding data for marketed compounds that act oneither huPPARα or huPPARγ. Binding and cotransfection data forrepresentative compounds of the present invention were compared withcorresponding data for reference compounds to determine the binding.

The concentration of test compound required to effect 50% maximalactivation of PPARα (IC₅₀α) and PPARγ (IC₅₀γ) was determined. Many ofthe compounds of the present invention are selective agonists for PPARγor are co-agonists of PPARα/PPARγ.

Evaluation of Triglyceride and Cholesterol Levels in HuapoAI TransgenicMice

Five to six week old male mice, transgenic for human apoAI[C57B1/6-tgn(apoa1)1rub, Jackson Laboratory, Bar Harbor, Me.] werehoused five per cage (10″×20″×8″ with aspen chip bedding) with food(Purina 5001) and water available at all times. After an acclimationperiod of 2 weeks, animals were individually identified by ear notches,weighed and assigned to groups based on body weight. Beginning thefollowing morning, mice were dosed daily by oral gavage for 7 days usinga 20 gauge, 1½″ curved disposable feeding needle. Treatments were testcompounds (30 mg/kg), a positive control (fenofibrate, 100 mg/kg) orvehicle [1% carboxymethylcellulose (w/v)/0.25% Tween80 (w/v); 0.2ml/mouse]. Prior to termination on day 7, mice were weighed and dosed.Three hours after dosing, animals were anesthetized by inhalation ofisoflurane (2–4%) and blood obtained via cardiac puncture (0.7–1.0 ml).Whole blood was transferred to serum separator tubes (Vacutainer SST),chilled on ice and permitted to clot. Serum, was obtained aftercentrifugation at 4° C. and frozen until analysis for triglycerides,total cholesterol, compound levels and serum lipoprotein profiled byfast protein liquid, chromatography (FPLC) coupled to an inlinedetection system. After sacrifice by cervical dislocation, the liver,heart and epididymal fat pads were excised and weighed.

The animals dosed with vehicle had average triglycerides values of about60 to 80 mg/dl, which were reduced by the positive control fenofibrate(33–58 mg/dl with a mean reduction of 37%). The animals dosed withvehicle have average total serum cholesterol values of about 140 to 180mg/dl, which were increased by fenofibrate (about 190 to 280 mg/dl witha mean elevation of 41%). When subject to FPLC analysis, pooled serafrom vehicle-treated hu apoAI transgenic mice had a high-densitylipoprotein cholesterol (HDLc) peak area which ranged from 47 v-sec to62 v-sec. Fenofibrate increased the amount of HDLc (68–96 v-sec with amean percent increase of 48%). Test compounds were evaluated in terms ofpercent increase in the area under the curve. Representative compoundsof the present invention were tested using the above method orsubstantially similar methods.

Evaluation of Glucose Levels in db/db Mice

Five week old male diabetic (db/db) mice [C57BlKs/j-m+/+Lepr(db),Jackson Laboratory, Bar Harbor, Me.] or lean littermates (db+) werehoused 6 per cage (10″×20″×8″ with aspen chip bedding) with food (Purina5015) and water available at all times. After an acclimation period of 2weeks, animals were individually identified by ear notches, weighed andbled via the tail vein for determination of initial glucose levels.Blood was collected (100 μl) from unfasted animals by wrapping eachmouse in a towel, cutting the tip of the tail with a scalpel, andmilking blood from the tail into a heparinized capillary tube balancedon the edge of the bench. Sample was discharged into a heparinizedmicrotainer with gel separator (VWR) and retained on ice. Plasma wasobtained after centrifugation at 4° C. and glucose was measuredimmediately. Remaining plasma was frozen until the completion of theexperiment, and glucose and triglycerides were assayed in all samples.Animals were grouped based on initial glucose levels and body weights.Beginning the following morning, mice were dosed daily by oral gavagefor 7 days using a 20 gauge, 1½″ curved disposable feeding needle.Treatments were test compounds (30 mg/kg), a positive control agent (30mg/kg) or vehicle [1% carboxymethylcellulose (w/v)/0.25% Tween80 (w/v);0.3 ml/mouse]. On day 7, mice were weighed and bled (tail vein) forabout 3 hours after dosing. Twenty-four hours after the 7^(th) dose(i.e., day 8), animals were bled again (tail vein). Samples obtainedfrom conscious animals on days 0, 7 and 8 were assayed for glucose.After 24 hour bleed, animals were weighed and dosed for the final time.Three hours after dosing on day 8, animals were anesthetized byinhalation of isoflurane, and blood obtained was via cardiac puncture(0.5–0.7 ml). Whole blood was transferred to serum separator tubes,chilled on ice and permitted to clot. Serum was obtained aftercentrifugation at 4° C. and frozen until analysis for compound levels.After sacrifice by cervical dislocation, the liver, heart and epididymalfat pads were excised and weighed.

The animals dosed with vehicle-had average triglycerides values of about170 to 230 mg/dl, which were reduced by the positive PPARγ control(about 70 to 120 mg/dl with a mean reduction of 50%). Male db/db miceare hyperglycemic (average glucose of about 680 to 730 mg/dl on the7^(th) day of treatment), while lean animals have average glucose levelsbetween about 190 and 230 mg/dl. Treatment with the positive controlagent reduced glucose significantly (about 350 to 550 mg/dl with a meandecrease towards normalization of 56%).

Glucose was measured colorimetrically by using commercially purchasedreagents (Sigma #315-500). According to the manufacturers, theprocedures were modified from published work (McGowan et al. Clin Chem,20:470–5 (1974) and Keston, A. Specific colorimetric enzymaticanalytical reagents for glucose. Abstract of papers 129th Meeting ACS,31C (1956).); and depend on the release of a mole of hydrogen peroxidefor each mole of analyte coupled with a color reaction first describedby Trinder (Trinder, P. Ann Clin Biochem, 6:24 (1969)). The absorbanceof the dye produced was linearly related to the analyte in the sample.The assays was further modified for use in a 96 well format. Standards(Sigma #339-11, Sigma #16-11, and Sigma #CC0534 for glucose,triglycerides and total cholesterol, respectively), quality controlplasma (Sigma # A2034), and samples-(2 or 5 μl well) were measured induplicate using 200 μl of reagent. An additional aliquot of sample,pipetted to a third well and diluted in 200 μl water, provided ai blankfor each specimen. Plates were incubated at room temperature (18, 15,and 10 minutes for glucose, triglycerides and total cholesterol,respectively) on a plate shaker and absorbance read at 500 nm (glucoseand total cholesterol) or 540 nm (triglycerides) on a plate reader.Sample absorbance was compared to a standard curve (100–800, 10–500, and100–400 mg/dl for glucose, triglycerides and total cholesterol,respectively). Values for the quality control sample wee consistentlywithin the expected range and the coefficient of variation for samplesis below 10%. All samples from an experiment were assayed at the sametime to minimize inter-assay variability.

Serum lipoproteins were separated and cholesterol was quantitated withan in-line detection system. Sample was applied to a Superose® 6 HR10/30 size exclusion column (Amersham Pharmacia Biotech) and eluted withphosphate buffered saline-EDTA at 0.5 ml/min. Cholesterol reagent (RocheDiagnostics Chol/HP 704036) at 0.16 ml/min was mixed with the columneffluent through a T-connection, and the mixture was passed through a 15m×0.5 mm id knitted tubing reactor immersed in a 37° C. water bath. Thecolored product produced in the presence of cholesterol was monitored inthe flow stream at 505 nm, and the analog voltage from the monitor wasconverted to a digital signal for collection and analysis. The change involtage corresponding to change in cholesterol concentration was plottedagainst time, and the area under the curve corresponding to the elutionof VLDL, LDL and HDL was calculated (Perkin Elmer Turbochrome software).

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details maybemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound represented by the following structural formula:

or pharmaceutically acceptable salts, hydrates, stereoisomers andsolvates thereof, wherein Z is —O— or —CO—.
 2. A compound represented bythe following structural formula

or pharmaceutically acceptable salts, hydrates and solvates thereof. 3.A compound selected from the group consisting of(S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

(S)-3-{4-[3 (Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[3-(Biphenyl-4-yloxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-(4-{3-[4-(4-Fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid, which is represented by the following structural formula:

(S)-3-{4-[4-(Biphenyl-4-yloxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid, which is represented by the following structural formula:

(S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid, which is represented by the following structural formula:

(S)-3-{4-[3-(4-Benzoyl-phenoxy)-prop-1-ynyl]-phenyl}-2-methoxy-propionicacid, which is represented by the following structural formula:

(S)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-prop-1-ynyl]-phenyl}-propionicacid, which is represented by the following structural formula:

(S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-2-fluoro-phenyl}-2-methoxy-propionicacid, which is represented by the following structural formula:

(S)-3-{4-[3-(4-Butyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid,which is represented by the following structural formula:

(S)-2-Methoxy-3-{4-[4-(4-phenoxy-phenoxy)-but-1-ynyl]-phenyl}-propionicacid, which is represented by the following structural formula:

(2S)-3-(4-{2-[4-(4-Fluoro-benzoyl)-phenoxy]-cyclopentyloxy}-phenyl)-2-methoxy-propionicacid, which is represented by the following structural formula:

(S)-3-{4-[5-(Biphenyl-4-yloxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid, which is represented by the following structural formula:

(S)-3-{4-[2-(4-Benzoyl-phenoxy)-ethoxy]-phenyl}-2-methoxy-propionicacid, which is represented by the following structural formula:

(S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[4-(4-Benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[4-(4-Benzoyl-phenoxy)-butyryl]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-{4-[5-(4-phenoxy-phenoxy)-pent-1-ynyl]-phenyl}-propionicacid, represented by the following structural formula:

(S)-3-{4-[5-(4-Benzoyl-phenoxy)-pent-1-ynyl]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-methoxy-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-{3-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

(S)-3-{4-[4-(4-Benzoyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[5-(4-Benzoyl-phenoxy)-pentanoyl]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

2-Methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-phenyl)-propionicacid, represented by the following structural formula:

3-(4-{4-[4-(Hydroxyimino-phenyl-methyl)-phenoxy]-but-1-ynyl}-phenyl)-2-methoxy-propionicacid, represented by the following structural formula:

2-Methoxy-3-{4-[1-methyl-2-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

3-{4-[2-(4-Benzoyl-phenoxy)-1-methyl-propoxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

Sodium3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionate,represented by the following structural formula:

3-{4-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-phenyl}-2S-methoxy-propionicacid, represented by the following structural formula:

3-{4-[3-(Biphenyl-4-yloxy)-cyclopentyloxy]-phenyl}-2S-methoxy-propionicacid, represented by the following structural formula:

Sodium(S)-2-methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hex-1-ynyl]-phenyl}-propionate,represented by the following structural formula:

Sodium(S)-3-{4-[6-(4-benzoyl-phenoxy)-hex-1-ynyl]-phenyl}-2-methoxy-propionate,represented by the following structural formula:

Sodium(S)-3-{4-[6-(biphenyl-4-yloxy)-hex-1-ynyl]-phenyl}-2-methoxy-propionate,represented by the following structural formula:

(S)-3-(4-{3-[4-(4-Hydroxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid, represented by the following structural formula:

Sodium(S)-2-methoxy-3-{4-[6-(4-phenoxy-phenoxy)-hexanoyl]-phenyl}-propionate,represented by the following structural formula:

(S)-2-Methoxy-3-{4-[3-(9-oxo-9H-fluoren-2-yloxy)-prop-1-ynyl]-phenyl}-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-7-yloxy)-prop-1-ynyl]-phenyl}-propionicacid, represented by the following structural formula:

(S)-3-{4-[3-(4-Dibenzofuran-2-yl-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[3-(4′-tert-Butyl-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(R)-2-Methoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

Sodium(S)-2-methoxy-3-{4-[3-(4-phenylacetyl-phenoxy)-cyclopentyloxy]-phenyl}-propionate,represented by the following structural formula:

Sodium(S)-3-(4-{3-[4-(2-fluoro-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionate,represented by the following structural formula:

(S)-2-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

Sodium(S)-3-{4-[4-(4-benzoyl-phenoxy)-but-1-ynyl]-phenyl}-2-methoxy-propionate,represented by the following structural formula:

Sodium(S)-3-{6-[3-(biphenyl-4-yloxy)-propoxy]-2′-methoxy-biphenyl-3-yl}-2-methoxy-propionate,represented by the following structural formula:

Sodium(S)-3-{4-[3-(4-benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionate,represented by the following structural formula:

Sodium(S)-2-methoxy-3-{4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-prop-1-ynyl]-phenyl}-propionate,represented by the following structural formula:

(S)-3-{4-[3-(4′-Hydroxy-biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

Sodium(S)-2-methoxy-3-(4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-prop-1-ynyl}-phenyl)-propionate,represented by the following structural formula:

(S)-4′-{3-[4-(2-Carboxy-2-methoxy-ethyl)-phenoxy]-propoxy}-biphenyl-4-carboxylicacid, represented by the following structural formula:

Sodium(S)-2-ethoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionate,represented by the following structural formula:

(S)-2-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid 2-dimethylamino-ethyl ester, represented by the followingstructural formula:

Sodium(S)-3-[4-(3-{4-[(4-fluoro-phenyl)-hydroxy-methyl]-phenoxy}-propoxy)-phenyl]-2-methoxy-propionate,represented by the following structural formula:

(S)-2-Methoxy-3-(4-{3-[4-(naphthalene-1-carbonyl)-phenoxy]-propoxy}-phenyl)-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-(4-{3-[4-(4-methyl-benzoyl)-phenoxy]-propoxy}-phenyl)-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-(4-{3-[4-(3-phenyl-propionyl)-phenoxy]-propoxy}-phenyl)-propionicacid, represented by the following structural formula:

(S)-3-(4-{3-[4-(2,4-Dimethoxy-benzoyl)-phenoxy]-propoxy}-phenyl)-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{3-Chloro-4-[3-(4-oxo-2-phenyl-4H-chromen-6-yloxy)-propoxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-(3-methoxy-4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}-phenyl)-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-(4-{3-[4-(3-methyl-butoxy)-phenoxy]-propoxy}-phenyl)-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-{4-[3-(4-phenethyloxy-phenoxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-2-chloro-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

Sodium(S)-3-{4-[3-(biphenyl-4-yloxy)-cyclohexyloxy]-phenyl}-2-methoxy-propionate,represented by the following structural formula:

Sodium(S)-3-{4-[3-(2-carboxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionate,represented by the following structural formula:

2-Methoxy-3-{2-methoxy-4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

3-{4-[3-(4-Phenoxy-phenoxy)-propoxy]-phenyl}-2-propoxy-propionic acid,represented by the following structural formula:

3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acid,represented by the following structural formula:

(S)-2-Isopropoxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

(S)-3-{4-[3-(4-Benzyl-phenoxy)-propoxy]-phenyl}-2-ethoxy-propionic acid,represented by the following structural formula:

(S)-3-{4-[3-(4-Benzoyl-phenoxy)-propoxy]-3-chloro-phenyl}-2-ethoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid,represented by the following structural formula:

(S)-2-Methoxy-3-{4-[3-(5,6,7,8-tetrahydro-naphthalen-2-yloxy)-propoxy]-phenyl}-propionicacid, represented by the following structural formula:

(S)-2-Methoxy-3-{4-[2-(4-phenoxy-phenoxy)-ethoxy]-phenyl}-propionicacid, represented by the following structural formula:

3-{3-[3-(Biphenyl-4-yloxy)-propoxy]-phenyl}-2-methoxy-propionic acid,represented by the following structural formula:

(S)-3-{4-[3-(3-Dimethylamino-phenoxy)-propoxy]-phenyl}-2-methoxy-propionicacid, represented by the following structural formula:

(S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-ethoxy-propionic acid,represented by the following structural formula:

(S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-propoxy-propionic acid,represented by the following structural formula:

or a pharmaceutically acceptable salts, hydrates and solvates of theforegoing compounds.
 4. A compound represented by the followingstructural formula:

or pharmaceutically acceptable salts, hydrates, stereoisomers andsolvates thereof, wherein: Ar is represented by a structural formulaselected from:

R₁ is —(CH₂)_(n)—CH(OR₂)—(CH₂)_(m)E, —(CH)═C(OR₂)—(CH₂)_(m)E,—(CH₂)_(n)—CH(Y)—(CH₂)_(m)E or —(CH)═C(Y)—(CH₂)_(m)E; wherein E isCOOR₃, C₁–C₃-alkylnitrile, carboxamide, sulfonamide or acylsulfonamideand wherein sulfonamide and acylsulfonamide are optionally substitutedwith one or more substituents independently selected from: C1–C6 alkyl,haloalkyl and aryl-C0–4-alkyl; R₂ is —H, an aliphatic group, asubstituted aliphatic group, an aromatic group, a substituted aromaticgroup, —COR₄, —COOR₄, —CONR₅R₆, —C(S)R₄, —C(S)OR₄ or —C(S)NR₅R₆; Y is—O—, —CH₂—, —CH₂CH₂— or —CH═CH— and is bonded to a carbon atom in PhenylRing A that is ortho to R₁; R₃–R₆ are independently —H, an aliphaticgroup, a substituted aliphatic group, an aromatic group or a substitutedaromatic group; n and m are independently 0, 1 or 2; Ring B-Z areindependently substituted or unsubstituted; X is —O—, —S—, —CH₂— or—C(O)—; Z is a covalent bond, —O—, (—CH₂)_(q)—, —CH(CH₃)(CH₂)_(q)—,—(CH₃)₂(CH₂)_(q)—, —(CH₂)_(q)CH(CH₃)—, —(CH₂)_(q)C(CH₃)₂—, —O(CH₂)_(q)—,—(CH₂) _(q)O—, —(CH₂)_(q)NH—, —(CH₂)_(q)NH—, —(CH₂)_(q)CHR₂₀—,—CHR₂₀(CH₂)_(q)—, —(CH₂)_(q)CR₂₀R₂₀—, —(CH₂)_(q)CR₂₀R₂₀—,—(CH₂)_(q)NR₂₀—, —NR₂₀(CH₂)_(q)—, —(CH₂)_(q)C(═NOH)—,—C(═NOH)(CH₂)_(q)—, —CH(OH)—(CH₂)_(q)—, —(CH₂)_(q)—CH(OH)—,—CO—(CH₂)_(q)—, —(CH₂)_(q)—CO—, —COO—(CH₂)_(q)—, —OCO—(CH₂)_(q)—,—(CH₂)_(q)—OCO—, —(CH₂)_(q)—COO—, —(CH₂)_(q)CO—NH—, —(CH₂)_(q)NH—CO—,—(CH₂)_(q)CONR₂₀—, —CONR₂₀(CH₂)_(q)—, —(CH₂)_(q)NR₂₀CO— or—NR₂₀CO(CH₂)_(q)—; q is , 0, 1, 2 or 3; and each R₂₀ is independently aC1–C5 alkyl group or a halogenated C1–C5 alkyl group; s is 0, 1 or 2;Ar₁ is a substituted or unsubstituted arylene group; W₆ is a covalentbond, —W₁—, —CH₂W₁— or —W₁CH₂—; W₇ is a covalent bond or CH₂—; and W₁ is—O—, —C(O)—, —OCH₂—, —CH₂—, —NR₈—, —NR₈CO—, —NR₈CH—, —C(═NOH)— or—CH(NR₇R₈)—.
 5. The compound of claim 4 wherein R₁ is—(CH₂)_(n)—CH(OR₂)—(CH₂)_(m)COOR₃, —(CH)═C(OR₂)—(CH₂)_(m)COOR₃,—(CH₂)_(n)—CH(Y)—(CH₂)_(m)COOR₃ or —(CH)═C(Y)—(CH₂)_(m)COOR₃.
 6. Thecompound of claim 5 wherein the compound is represented by the followingstructural formula:

wherein s is 0 or 1 and W₆ is a covalent bond, —O—, —CH₂O— or —OCH₂—. 7.A pharmaceutical composition comprising the compound of claim 2 or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier.
 8. A method for loweringblood-glucose in a subject comprising the step of administering to thesubject an effective amount of the compound of claim 2.